U.S. patent application number 13/971374 was filed with the patent office on 2014-02-27 for substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. The applicant listed for this patent is Dennis FIEGEN, Christian GNAMM, Sandra HANDSCHUH, Thorsten OOST, Stefan PETERS, Gerald Juergen ROTH. Invention is credited to Dennis FIEGEN, Christian GNAMM, Sandra HANDSCHUH, Thorsten OOST, Stefan PETERS, Gerald Juergen ROTH.
Application Number | 20140057920 13/971374 |
Document ID | / |
Family ID | 46963419 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140057920 |
Kind Code |
A1 |
OOST; Thorsten ; et
al. |
February 27, 2014 |
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; Dennis; (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 |
OOST; Thorsten
FIEGEN; Dennis
GNAMM; Christian
HANDSCHUH; Sandra
PETERS; Stefan
ROTH; Gerald Juergen |
Biberach an der Riss
Biberach an der Riss
Biberach an der Riss
Biberach an der Riss
Biberach an der Riss
Biberach an der Riss |
|
DE
DE
DE
DE
DE
DE |
|
|
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
46963419 |
Appl. No.: |
13/971374 |
Filed: |
August 20, 2013 |
Current U.S.
Class: |
514/252.03 ;
514/300; 514/333; 514/335; 514/336; 514/337; 514/338; 514/340;
514/341; 514/343; 514/350; 544/238; 546/121; 546/256; 546/261;
546/269.1; 546/270.1; 546/274.4; 546/275.7; 546/278.4; 546/281.1;
546/283.4; 546/298 |
Current CPC
Class: |
C07D 513/04 20130101;
C07D 413/12 20130101; C07D 213/82 20130101; C07D 405/14 20130101;
A61P 17/00 20180101; A61P 11/06 20180101; C07D 405/04 20130101;
A61P 27/14 20180101; A61P 35/00 20180101; A61P 11/00 20180101; C07D
401/12 20130101; C07D 471/04 20130101; A61P 19/02 20180101; A61P
37/00 20180101; A61P 43/00 20180101; A61P 29/00 20180101; C07D
405/06 20130101; C07D 409/14 20130101; A61P 37/08 20180101; C07D
409/12 20130101; A61P 1/04 20180101; A61P 31/00 20180101 |
Class at
Publication: |
514/252.03 ;
546/298; 514/350; 546/283.4; 514/336; 546/261; 514/335; 546/256;
514/333; 546/269.1; 514/340; 544/238; 514/341; 546/274.4;
546/278.4; 514/343; 546/121; 514/300; 546/275.7; 546/281.1;
514/337; 546/270.1; 514/338 |
International
Class: |
C07D 213/82 20060101
C07D213/82; C07D 405/14 20060101 C07D405/14; C07D 413/12 20060101
C07D413/12; C07D 513/04 20060101 C07D513/04; C07D 405/04 20060101
C07D405/04; C07D 409/12 20060101 C07D409/12; C07D 409/14 20060101
C07D409/14; C07D 405/06 20060101 C07D405/06; C07D 471/04 20060101
C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 23, 2012 |
EP |
12 181 541.9 |
Claims
1. A compound of formula 1 ##STR00234## wherein A 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, S and
(O.sup.-N.sup.+); or a ring system of two fused five- or
six-membered, aromatic heterorings, 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).sub.2S and
(O.sup.-N.sup.+); R.sup.1a is H, C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl-, C.sub.3-6-cyloalkyl-, NC--,
C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.3-6-cycloalkyl-(O)S--, C.sub.3-6-cycloalkyl-(O).sub.2S--,
C.sub.1-4-haloalkyl-(O)S--, C.sub.1-4-haloalkyl-(O).sub.2S--,
H.sub.2N(O).sub.2S--, R.sup.1a.1--C.sub.1-4-alkyl-, R.sup.1a.1;
R.sup.1a.1 is 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 and O; optionally substituted with O.dbd. or
C.sub.1-4-Alkyl-; R.sup.1b is H, O.dbd., halogen,
C.sub.1-4-alkyl-O-- or C.sub.1-4-alkyl-; or R.sup.1a and R.sup.1b
are together C.sub.2-4-alkylene forming a carbocyclic heteroring,
wherein one element of the ring is replaced by (O).sub.2S; R.sup.2
is C.sub.1-6-alkyl-, C.sub.1-6-haloalkyl-,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl- or a ring selected from the
group consisting of C.sub.3-6-cycloalkyl-,
C.sub.3-6-halocycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkyl-,
C.sub.3-6-halocycloalkyl-C.sub.1-4-alkyl-; wherein one element of
the above mentioned rings is optionally replaced by O; R.sup.3 is
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; each element of one of the rings
optionally to substituted with a residue selected from the group
consisting of C.sub.1-4-alkyl-, C.sub.3-6-cycloalkyl-,
C.sub.1-4-haloalkyl- and halogen; R.sup.5 is H, C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl- and C.sub.3-6-cycloalkyl-; R.sup.6 is H,
C.sub.1-4-alkyl-; R.sup.7 is H, C.sub.1-4-alkyl-; or R.sup.6 and
R.sup.7 are together C.sub.2-5-alkylene forming a carbocyclic ring;
or a salt thereof.
2. A compound of formula I, according to claim 1, wherein A is
phenyl or a five- or six-membered, aromatic heteroring, wherein one
or two or three elements are replaced by an element selected
independent from each other from the group consisting of N, O, S
and (O.sup.-N.sup.+); or R.sup.1a is H, C.sub.1-4-alkyl-, NC--,
C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--,
H.sub.2N(O).sub.2S--, R.sup.1a.1--C.sub.1-4-alkyl-, R.sup.1a.1;
R.sup.1a.1 is a five- or six-membered, aromatic or non-aromatic
heteroring, wherein one or two elements are replaced by an element
selected independent from each other from the group consisting of N
and O; optionally substituted with O.dbd.; R.sup.1b is H, haolgen
or C.sub.1-4-alkyl-; or R.sup.1a and R.sup.1b are together
C.sub.2-4-alkylene forming a carbocyclic ring, wherein one element
of the ring is replaced by (O).sub.2S; R.sup.2 is C.sub.1-6-alkyl-,
C.sub.1-6-haloalkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl- or a ring
selected from the group consisting of C.sub.3-6-cycloalkyl-,
C.sub.3-6-halocycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkyl-,
C.sub.3-6-halocycloalkyl-C.sub.1-4-alkyl-; wherein one element of
the above mentioned rings is optionally replaced by O; R.sup.3 is
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 and O; wherein one or two elements of one of the
rings are optionally substituted with a residue selected from the
group consisting of C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl- and
halogen; R.sup.5 is H; R.sup.6 is H; R.sup.7 is H; or a salt
thereof.
3. A compound of formula 1, according to claim 1, wherein A is
phenyl, pyrazolyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl,
thiophenyl; R.sup.1a is H, methyl, NC--, Me(O)S--, Me(O).sub.2S--,
Et(O).sub.2S--, H.sub.2N(O).sub.2S--, imidazolidin-onyl,
pyrrolidinon-H.sub.2C--, imidazol-H.sub.2C--; R.sup.1b is H; or
R.sup.1a and R.sup.1b are together C.sub.3-alkylene forming a
carbocyclic ring, wherein one element of the ring is replaced by
(O).sub.2S; R.sup.2 is C.sub.1-6-alkyl-, C.sub.3-6-cycloalkyl-,
C.sub.3-6-cycloalkyl-H.sub.2C--, tetrahydrofuranyl,
tetrahydrofuran-H.sub.2C--, each optionally substituted with one or
two residues selected from the group consisting of F; R.sup.3 is
methyl; R.sup.4 is phenyl or pyridinyl, both optionally substituted
with a residue selected from the group consisting of F.sub.2HC--,
F.sub.3C--; R.sup.5 is H; R.sup.6 is H; R.sup.7 is H; or a salt
thereof.
4. A compound of formula I, according to claim 1, wherein A is
phenyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl, thiophenyl;
R.sup.1a is H, methyl, NC--, Me(O)S--, Me(O).sub.2S--,
Et(O).sub.2S--, H.sub.2N(O).sub.2S--, imidazolidin-onyl,
pyrrolidinon-H.sub.2C--, imidazol-H.sub.2C--; or R.sup.1a and
R.sup.1b are together C.sub.3-alkylene forming a carbocyclic ring,
wherein one element of the ring is replaced by (O).sub.2S; R.sup.2
is ethyl, n-propyl, i-propyl, 1-methyl-propyl, 1-ethyl-propyl,
cyclopropanyl, cyclobutanyl, cyclopentanyl, tetrahydrofuranyl, each
optionally substituted with one or two F; R.sup.3 is methyl;
R.sup.4 is phenyl or pyridinyl, both substituted with a residue
selected from the group consisting of F.sub.2HC--, F.sub.3C--;
R.sup.5 is H; R.sup.6 is H; R.sup.7 is H; or a salt thereof.
5. A compound of formula 1, according to claim 1, wherein A is
phenyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl, thiophenyl;
R.sup.1a is H, methyl, NC--, Me(O)S--, Me(O).sub.2S--,
Et(O).sub.2S--, H.sub.2N(O).sub.2S--, imidazolidin-onyl,
pyrrolidinon-H.sub.2C--, imidazol-H.sub.2C--; R.sup.1b is H;
R.sup.2 is i-propyl; R.sup.3 is methyl; R.sup.4 is phenyl or
pyridinyl, both substituted with a residue selected from the group
consisting of F.sub.2HC--, F.sub.3C--; R.sup.5 is H; R.sup.6 is H;
R.sup.7 is H; or a salt thereof.
6. A method for the treatment of asthma and allergic diseases,
gastrointestinal inflammatory diseases, eosinophilic diseases,
chronic obstructive pulmonary disease, infection by pathogenic
microbes and rheumatoid arthritis which comprises administering to
a host suffering from one of said conditions a therapeutically
effective amount of a compound of the formula I according to claim
1 or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of formula 1
according to claim 1 or a pharmaceutically active salt thereof and
a pharmaceutically acceptable carrier.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] The following references describe neutrophil elastase
inhibitors with a 2-pyridone central core: WO04043924, WO05026123,
WO05026124, WO06098683, WO06098684, WO07129962, WO10094964,
WO11039528. [0003] The following references describe neutrophil
elastase inhibitors with a 2-pyrazinone central core: WO07129963,
WO09061271, WO09058076, WO11110852. [0004] For a review on various
inhibitors of neutrophil elastase see: P. Sjo (Future Med. Chem.
2012, 4, 651-660).
BRIEF SUMMARY OF THE INVENTION
[0005] 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.
[0006] 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.
[0007] 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).
[0008] 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).
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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).
[0013] 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).
[0014] 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.
[0015] 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).
[0016] 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
[0017] Compounds of formula 1
##STR00002##
wherein [0018] A 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, S and (O.sup.-N.sup.+); or a ring system of two
fused five- or six-membered, aromatic heterorings, 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).sub.2S
and (O.sup.-N.sup.+); [0019] R.sup.1a is H, C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl-, C.sub.3-6-cyloalkyl-, NC--,
C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.3-6-cycloalkyl-(O)S--, C.sub.3-6-cycloalkyl-(O).sub.2S--,
C.sub.1-4-haloalkyl-(O)S--, C.sub.1-4-haloalkyl-(O).sub.2S--,
H.sub.2N(O).sub.2S--, R.sup.1a.1--C.sub.1-4-alkyl-, R.sup.1a.1;
[0020] R.sup.1a.1 is 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 and O; optionally substituted with O.dbd.
or C.sub.1-4-Alkyl-; [0021] R.sup.1b is H, O.dbd., halogen,
C.sub.1-4-alkyl-O-- or C.sub.1-4-alkyl-, preferably H, F or methyl;
or R.sup.1a and R.sup.1b are together C.sub.2-4-alkylene forming a
carbocyclic heteroring, wherein one element of the ring is replaced
by (O).sub.2S; [0022] R.sup.2 is C.sub.1-6-alkyl-,
C.sub.1-6-haloalkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl- or a ring
selected from the group consisting of C.sub.3-6-cycloalkyl-,
C.sub.3-6-halocycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkyl-,
C.sub.3-6-halocycloalkyl-C.sub.1-4-alkyl-; wherein one element of
the above mentioned rings is optionally replaced by O; [0023]
R.sup.3 is C.sub.1-4-alkyl-; [0024] 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; each element of one of the
rings optionally substituted with a residue selected from the group
consisting of C.sub.1-4-alkyl-, C.sub.3-6-cycloalkyl-,
C.sub.1-4-haloalkyl- and halogen; [0025] R.sup.5 is H,
C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl- and C.sub.3-6-cycloalkyl-;
[0026] R.sup.6 is H, C.sub.1-4-alkyl-; [0027] R.sup.7 is H,
C.sub.1-4-alkyl-; or R.sup.6 and R.sup.7 are together
C.sub.2-5-alkylene forming a carbocyclic ring; or a salt
thereof.
Preferred Embodiments
[0028] Preferably A 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, S and (O.sup.-N.sup.+);
[0029] Preferably A is a ring system of two fused five- or
six-membered, aromatic heterorings, wherein one, two or three
elements are replaced by an element selected independent from is
each other from the group consisting of N, O, S and
(O.sup.-N.sup.+);
[0030] Preferred are the above compounds of formula I, wherein
[0031] A 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
and O; [0032] R.sup.1a is C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--; [0033] R.sup.1b is H, halogen,
C.sub.1-4-alkyl-O-- or C.sub.1-4-alkyl-, preferably H, F or methyl;
[0034] R.sup.2 is C.sub.1-6-alkyl- or C.sub.3-6-cycloalkyl-,
wherein one element of the above mentioned rings is optionally
replaced by O; [0035] R.sup.3 is C.sub.1-4-alkyl-; [0036] R.sup.4
is phenyl or a 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; each element of one of
the rings optionally substituted with C.sub.1-4-haloalkyl-; or a
salt thereof and R.sup.5, R.sup.6 and R.sup.7 have the above given
meaning, preferably they are all H.
[0037] Preferred are the above compounds of formula 1, wherein
[0038] A 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
and 0; [0039] R.sup.1a is C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--; preferably H.sub.3C--(O)S-- or
H.sub.3C--(O).sub.2S--; [0040] R.sup.1b is H, F or methyl; [0041]
R.sup.2 is C.sub.1-6-alkyl- or C.sub.3-6-cycloalkyl-, wherein one
element of the above mentioned rings is optionally replaced by O;
[0042] R.sup.3 is C.sub.1-4-alkyl-; preferably methyl; [0043]
R.sup.4 is phenyl, optionally substituted with
C.sub.1-4-haloalkyl-, preferably HF.sub.2C-- or F.sub.3C; or a salt
thereof and R.sup.5, R.sup.6 and R.sup.7 have the above given
meaning, preferably they are all H.
[0044] Preferred are the above compounds of formula I, wherein
[0045] A is phenyl or pyridinyl; [0046] R.sup.1a is
C.sub.1-4-alkyl-(O).sub.2S--; preferably H.sub.3C--(O).sub.2S--;
[0047] R.sup.1b is H, F or methyl; [0048] R.sup.2 is methyl, ethyl,
n-propyl, i-propyl or sec-butyl; preferably ethyl or i-propyl;
[0049] R.sup.3 is methyl; [0050] R.sup.4 is phenyl, optionally
substituted with HF.sub.2C-- or F.sub.3C, preferably HF.sub.2C--;
or a salt thereof and R.sup.5, R.sup.6 and R.sup.7 have the above
given meaning, preferably they are all H.
[0051] Preferred are the above compounds of formula 1, wherein
[0052] A is phenyl or a five- or six-membered, aromatic heteroring,
wherein one or two or three elements are replaced by an element
selected independent from each other from the group consisting of
N, O, S and (O.sup.-N.sup.+); or [0053] R.sup.1a is H,
C.sub.1-4-alkyl-, NC--, C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--, H.sub.2N(O).sub.2S--, R.sup.1a.1
C.sub.1-4-alkyl-, R.sup.1a.1; [0054] R.sup.1a.1 is a five- or
six-membered, aromatic or non-aromatic heteroring, wherein one or
two elements are replaced by an element selected independent from
each other from the group consisting of N and O; optionally
substituted with O.dbd.; [0055] R.sup.1b is H, halogen or
C.sub.1-4-alkyl-, preferably H, F or methyl or R.sup.1a and
R.sup.1b are together C.sub.2-4-alkylene forming a carbocyclic
ring, wherein one element of the ring is replaced by (O).sub.2S;
[0056] R.sup.2 is C.sub.1-6-alkyl-, C.sub.1-6-haloalkyl-,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl- or a ring selected from the
group consisting of C.sub.3-6-cycloalkyl-,
C.sub.3-6-halocycloalkyl-, C.sub.3-6-cycloalkyl-C.sub.1-4-alkyl-,
C.sub.3-6-halocycloalkyl-C.sub.1-4-alkyl-; wherein one element of
the above mentioned rings is optionally replaced by 0; [0057]
R.sup.3 is C.sub.1-4-alkyl-; [0058] 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 and O; wherein one or two elements of one
of the rings are optionally substituted with a residue selected
from the group consisting of C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-
and halogen; or a salt thereof and R.sup.5, R.sup.6 and R.sup.7
have the above given meaning, preferably they are all H.
[0059] Preferred are the above compounds of formula 1, wherein
[0060] A is phenyl, pyrazolyl, oxadiazolyl, pyridinyl,
pyridin-N-oxidyl, thiophenyl; [0061] R.sup.1a is H, methyl, NC--,
Me(O)S--, Me(O).sub.2S--, Et(O).sub.2S--, H.sub.2N(O).sub.2S--,
imidazolidin-onyl, pyrrolidinon-H.sub.2C--, imidazol-H.sub.2C--;
[0062] R.sup.1b is H; or R.sup.1a and R.sup.1b are together
C.sub.3-alkylene forming a carbocyclic ring, wherein one element of
the ring is replaced by (O).sub.2S; [0063] R.sup.2 is
C.sub.1-6-alkyl-, C.sub.3-6-cycloalkyl-,
C.sub.3-6-cycloalkyl-H.sub.2C--, tetrahydrofuranyl,
tetrahydrofuran-H.sub.2C--, each optionally substituted with one or
two residues selected from the group consisting of F; [0064]
R.sup.3 is methyl; [0065] R.sup.4 is phenyl or pyridinyl, both
optionally substituted with a residue selected from the group
consisting of F.sub.2HC--, F.sub.3C--; or a salt thereof and
R.sup.5, R.sup.6 and R.sup.7 have the above given meaning,
preferably they are all H.
[0066] Preferred are the above compounds of formula 1, wherein
[0067] A is phenyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl,
thiophenyl; [0068] R.sup.1a is H, methyl, NC--, Me(O)S--,
Me(O).sub.2S--, Et(O).sub.2S--, H.sub.2N(O).sub.2S--,
imidazolidin-onyl, pyrrolidinon-H.sub.2C--, imidazol-H.sub.2C--;
[0069] R.sup.1b is H; or R.sup.1a and R.sup.1b are together C.sub.3
alkylene forming a carbocyclic ring, wherein one element of the
ring is replaced by (O).sub.2S; [0070] R.sup.2 is ethyl, n-propyl,
i-propyl, 1-methyl-propyl, 1-ethyl-propyl, cyclopropanyl,
cyclobutanyl, cyclopentanyl, tetrahydrofuranyl, each optionally
substituted with one or two F; [0071] R.sup.3 is methyl; [0072]
R.sup.4 is phenyl or pyridinyl, both substituted, preferably in
meta position, with a residue selected from the group consisting of
F.sub.2HC--, F.sub.3C--; or a salt thereof and R.sup.5, R.sup.6 and
R.sup.7 have the above given meaning, preferably they are all
H.
[0073] Preferred are the above compounds of formula 1, wherein
[0074] A is phenyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl,
thiophenyl; [0075] R.sup.1a is H, methyl, NC--, Me(O)S--,
Me(O).sub.2S--, Et(O).sub.2S--, H.sub.2N(O).sub.2S--,
imidazolidin-onyl, pyrrolidinon-H.sub.2C--, imidazol-H.sub.2C--;
[0076] R.sup.1b is H; [0077] R.sup.2 is i-propyl; [0078] R.sup.3 is
methyl; [0079] R.sup.4 is phenyl or pyridinyl, both substituted,
preferably in meta position, with a residue selected from the group
consisting of F.sub.2HC--, F.sub.3C--; or a salt thereof and
R.sup.5, R.sup.6 and R.sup.7 have the above given meaning,
preferably they are all H.
[0080] Preferred are the above compounds of formula 1, wherein
[0081] A is phenyl or pyridinyl; [0082] R.sup.1a is Me(O).sub.2S--;
[0083] R.sup.1b is H; and R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 have the above given meaning.
[0084] 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.
[0085] From the above mentioned compounds those are preferred
wherein R.sup.4 is
##STR00003##
[0086] From the above mentioned compounds those are preferred
wherein R.sup.4 is
##STR00004##
[0087] From the above mentioned compounds those are preferred
wherein R.sup.4 is
##STR00005##
Used Terms and Definitions
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] For example, the term "3-carboxypropyl-group" represents the
following substituent:
##STR00006##
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:
##STR00007##
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] When in the claimed ring system A (e.g. SA) the two residues
R.sup.1a and R.sup.1b are "together a C.sub.2-4-alkylene forming a
carbocyclic ring, wherein one element of the ring is replaced by
(O).sub.2S; rings similar to example SB are meant in this case
R.sup.1a and R.sup.1b are in ortho position to each other.
##STR00008##
[0100] The term halogen generally denotes fluorine, chlorine,
bromine and iodine.
[0101] 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).
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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, ethylenediamine, 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, ethanesulfonic 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).
[0106] 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.
[0107] 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.
[0108] 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)--.
[0109] The term "C.sub.n-m-alkylene" wherein n is an integer 2 or 3
and m is 4 or 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.2-4-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)--.
[0110] 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--.
[0111] The term "C.sub.3-n-cycloalkyl", wherein n is an integer
from 4 to 6, either alone or in is combination with another radical
denotes a cyclic, saturated, unbranched hydrocarbon radical with 3
to n C atoms. For example the term C.sub.3-6-cycloalkyl includes
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0112] 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.
[0113] 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.
[0114] 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.+, 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 non-aromatic heteroring, the detailed
definition is restricting the above mentioned definition.
[0115] 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:
##STR00009## ##STR00010## ##STR00011##
[0116] 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.
[0117] 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:
##STR00012##
[0118] 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.
[0119] 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:
##STR00013## ##STR00014##
[0120] 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"
##STR00015##
Preparation
[0121] 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.
##STR00016##
[0122] Starting material I can be prepared as described in
US2003/87940.
[0123] 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.
[0124] 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) or
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) or propylphosphonic anhydride (PPA), and
in the presence of a base, for example triethylamine,
diisopropylethylamine (DIPEA, Hunig's base) or N-methyl-morpholine,
in an organic solvent, for example dichloromethane, acetonitrile,
N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) 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.
[0125] The bromination (Step C, X=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 is acetic acid, dichloromethane,
methanol, acetonitrile, tetrahydrofuran or mixtures thereof. The
iodination (Step C, X=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.
[0126] 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.
[0127] 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.
##STR00017##
[0128] 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).
[0129] 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 Gradient/Solvent %
Sol % Sol Flow Temp Time [min] [H2O, 0.1% NH3] [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 Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H2O, 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 Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H2O, 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_006 Column: Sunfire C18, 3
.times. 30 mm, 2.5 .mu.m Column Supplier: Waters Gradient/Solvent %
Sol % Sol Flow Temp Time [min] [H2O, 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: Z002_007 Column:
Sunfire C18, 3 .times. 30 mm, 2.5 .mu.m Column Supplier: Waters
Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 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 Gradient/Solvent % Sol % Sol Flow Temp Time [min]
[H2O, 0.1% NH3] [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 Gradient/Solvent % Sol % Sol Flow Temp Time [min]
[H2O, 0.1% NH3] [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 Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H2O, 0.1% NH3] [Acetonitrile] [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: Z012_S04 Column: XBridge C18, 3
.times. 30 mm, 2.5 .mu.m Column Supplier: Waters Gradient/Solvent %
Sol % Sol Flow Temp Time [min] [H2O, 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: Z018_S04
Column: Sunfire, 3 .times. 30 mm, 2.5 .mu.m Column Supplier: Waters
Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA]
[Acetonitrile] [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 Gradient/Solvent % Sol [H2O, % Sol Flow
Temp Time [min] 0.1% NH4OH] [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 Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time
[min] 0.1% NH4OH] [Acetonitrile] [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 Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1%
NH4OH] [Acetonitrile] [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
Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 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
Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% NH4OH]
[Acetonitrile] [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: X012_S01 Column:
Xbridge BEH C18, 2.1 .times. 30 mm, 1.7 .mu.m Column Supplier:
Waters Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1%
TFA] [Acetonitrile] [ml/min] [.degree. C.] 0.0 99 1 1.6 60 0.02 99
1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60 Method Name: 005_CA01
Column: Sunfire C18_3.0 .times. 30 mm, 2.5 .mu.m Column Supplier:
Waters Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1%
TFA] [Acetonitrile] [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: 001_CA07
Column: Sunfire C18_2.1 .times. 50 mm, 2.5 .mu.m Column Supplier:
Waters % Sol Gradient/Solvent % Sol [Acetonitrile Flow Temp Time
[min] [H2O 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: 002_CA07 Column: XBridge BEH C18_3.0 .times. 30 mm, 1.7 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol [H2O % Sol Flow Temp
Time [min] 0.1% NH4OH] [Acetonitrile] [ml/min] [.degree. C.] 0.0
95.0 5.0 1.5 60.0 0.7 0.1 99.9 1.5 60.0 0.8 0.1 99.9 1.5 60.0 0.81
95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0 Method Name: CD00 Column:
XBridge Shield RP C18, 50 .times. 2.1 mm, 5 .mu.m Column Supplier:
Waters % Sol Gradient/Solvent [H.sub.2O, 10 mmol % Sol Flow Temp
Time [min] (NH.sub.4).sub.2CO.sub.3] [Acetonitrile] [ml/min]
[.degree. C.] 0.00 100 0 0.6 50.0 0.40 100 0 0.6 50.0 3.40 20 80
0.6 50.0 3.85 0 100 0.6 50.0 3.86 100 0 0.6 50.0 Method Name:
X011_S03 Column: Xbridge BEH C18, 2.1 .times. 30 mm, 1.7 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H2O, 0.1% NH3] [Acetonitrile] [ml/min] [.degree. C.] 0.00 95
5 1.3 60 0.02 95 5 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60
Method Name: 0-30AB Column: Venusil XBP-C18, 50 .times. 2.1 mm, 5
.mu.m Column Supplier: Bonna Agela % Sol % Sol Gradient/Solvent
[H.sub.2O, [MeCN, Flow Temp Time [min] 0.0375% TFA] 0.18% TFA]
[ml/min] [.degree. C.] 0.00 100 0 1.0 50 2.60 70 30 1.0 50 2.70 70
30 1.0 50 2.71 100 0 1.0 50 3.00 100 0 1.0 50
Method Name: 0-30HPLC Column: XBridge Shield RP C18,, 50 .times.
2.1 mm, 5 .mu.m Column Supplier: Waters % Sol Gradient/Solvent
[H.sub.2O, 10 mmol % Sol Flow Temp Time [min]
(NH.sub.4).sub.2CO.sub.3] [MeCN] [ml/min] [.degree. C.] 0.00 100 0
0.8 40 4.40 70 30 0.8 40 5.20 70 30 0.8 40 5.22 100 0 0.8 40 5.90
100 0 0.8 40 Method Name: 5-95AB Column: Chromolith Flash RP-18e,
25 .times. 2 mm, 1.5 .mu.m Column Supplier: Merck Milipore % Sol %
Sol Gradient/Solvent [H.sub.2O, [MeCN, Flow Temp Time [min] 0.0375%
TFA] 0.18% TFA] [ml/min] [.degree. C.] 0.00 95 5 1.5 40 0.70 5 95
1.5 40 1.15 5 95 1.5 40 1.16 95 5 1.5 40 1.60 5 95 1.5 40
Preparation 1
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxy-
lic acid 4-methanesulfonyl-benzylamide
##STR00018##
[0130] 1a 5-Bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00019##
[0132] 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.sub.--002).
1b
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carb-
oxylic acid
##STR00020##
[0134] To a solution of
5-bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid
(preparation 1a, 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
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.sub.--001).
1c
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carb-
oxylic acid 4-methanesulfonyl-benzylamide
##STR00021##
[0136] A solution of
6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid (preparation 1b, 3.00 g, 10.1 mmol), HBTU (4.00 g, 10.5
mmol) and 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.sub.--001).
Preparation 2
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxy-
lic acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00022##
[0138] Preparation 2 is prepared following the procedure for
preparation 1, substituting 4-methylsulfonylbenzylamine
hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
ESI mass spectrum: [M+H].sup.+=466; Retention time HPLC: 1.09 min
(V003.sub.--003)
Preparation 3
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
##STR00023##
[0139] 3a: 3-Dimethylaminomethylene-6-methyl-pyran-2,4-dione
##STR00024##
[0141] 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 stiffing 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.sub.--007).
3b: 1-Isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00025##
[0143] A solution of
3-dimethylaminomethylene-6-methyl-pyran-2,4-dione (preparation 3a,
10.00 g, 38.6 mmol based on 70% purity), isopropylamine (5.00 mL,
58.4 mmol) and sodium tert-butoxide (5.50 g, 57.2 mmol) in ethanol
(20 mL) is heated for 18 h at 90.degree. C. The reaction mixture is
evaporated under reduced pressure, treated with water and extracted
with dichloromethane. The aqueous layer is acidified with 4 N
aqueous HCl and extracted with dichloromethane. The combined
organic layer is washed with water, dried over Na.sub.2SO.sub.4 and
evaporated under reduced pressure. Yield: 7.16 g; ESI mass
spectrum: [M+H].sup.+=196; Retention time HPLC: 0.71 min
(Z002.sub.--006).
3c:
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00026##
[0145] To a solution of
1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid
(preparation 3b, 1.50 g, 6.92 mmol based on 90% purity) in glacial
acetic acid (10 ml) is added at room temperature bromine (0.60 mL,
11.7 mmol). After stiffing for 3 d at room temperature, additional
bromine (1.00 mL, 19.5 mmol) is added to the reaction mixture and
stirring is continued for 2 h at room temperature. The reaction
mixture is diluted with water. Upon addition of dichloromethane a
precipitate forms which is filtered off and dried. Yield: 2.55 g;
ESI mass spectrum: [M+H].sup.+=274 (bromine isotope pattern);
Retention time HPLC: 0.76 min (Z002.sub.--002).
3d:
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-py-
ridine-3-s carboxylic acid
##STR00027##
[0147] Preparation 3d is prepared following the procedure for
preparation 4, substituting 3-(difluoromethyl)phenylboronic acid
with 3-(trifluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=340; Retention time HPLC: 0.99 min (Z018_S04).
Preparation 4
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid
##STR00028##
[0149] A mixture of
5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (preparation 3c, 3.00 g, 8.32 mmol, based on 76% purity),
3-(difluoromethyl)-phenylboronic acid (2.30 g, 13 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (690
mg, 0.94 mmol) and 2 M aqueous K.sub.2CO.sub.3 solution (10 mL, 20
mmol) in acetonitrile (20 mL) is heated for 2 h at 75.degree. C.
The reaction mixture is diluted with methanol and purified by
preparative reversed phase HPLC (XBridge, gradient of acetonitrile
in water, 0.3% NH.sub.4OH, 30.degree. C.). Yield: 1.46 g (55% of
theory); ESI mass spectrum: [M+H].sup.+=322; Retention time HPLC:
0.92 min (Z018_S04).
Preparation 5
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide
##STR00029##
[0151] A solution of
5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (preparation 3c, 0.50 g, 1.82 mmol), HBTU (0.77 g, 2.03 mmol),
DIPEA (0.76 mL, 4.47 mmol) in DMF (2 mL) is stirred for 10 min.
Then, 4-methylsulfonylbenzylamine hydrochloride (0.64 g, 2.89 mmol)
is added and the reaction mixture is stirred for 72 h at room
temperature. 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: 0.25 g (31% of theory); ESI mass
spectrum: [M+H].sup.+=441 (bromine isotope pattern); Retention time
HPLC: 1.16 min (Z002.sub.--006).
Preparation 6
1-Cyclopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyri-
dine-3-carboxylic acid
##STR00030##
[0152] 6a:
1-Cyclopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00031##
[0154] Preparation 6a is prepared following the procedure for
preparation 3b, substituting isopropylamine with cyclopropylamine.
ESI mass spectrum: [M+H].sup.+=194; Retention time HPLC: 0.53 min
(Z002.sub.--002).
6b:
5-Bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00032##
[0156] Preparation 6b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 6a.
ESI mass spectrum: [M+H].sup.+=272 (bromine isotope pattern);
Retention time HPLC: 0.79 min (Z002.sub.--002).
6c:
1-Cyclopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro--
pyridine-3-carboxylic acid
##STR00033##
[0158] Preparation 6c is prepared following the procedure for
preparation 4, substituting preparation 3c with preparation 6b and
3-(difluoromethyl)phenylboronic acid with
3-(trifluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=338; Retention time HPLC: 0.63 min
(Z003.sub.--001).
Preparation 7
1-Cyclobutyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid
##STR00034##
[0159] 7a:
1-Cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00035##
[0160] Preparation 7a is prepared following the procedure for
preparation 3b, substituting isopropylamine with cyclobutylamine.
ESI mass spectrum: [M+H].sup.+=208; Retention time HPLC: 0.62 min
(Z002.sub.--002).
7b:
5-Bromo-1-cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00036##
[0162] Preparation 7b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 7a.
ESI mass spectrum: [M+H].sup.+=286 (bromine isotope pattern);
Retention time HPLC: 0.86 min (Z002.sub.--002).
7c:
1-Cyclobutyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-p-
yridine-3-carboxylic acid
##STR00037##
[0164] Preparation 7c is prepared following the procedure for
preparation 4, substituting preparation 3c with preparation 7b and
3-(difluoromethyl)phenylboronic acid with
3-(trifluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=352; Retention time HPLC: 0.67 min
(Z003.sub.--001).
Preparation 8
1-Cyclopentyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyri-
dine-3-carboxylic acid
##STR00038##
[0165] 8a:
1-Cyclopentyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00039##
[0167] Preparation 8a is prepared following the procedure for
preparation 3b, substituting isopropylamine with cyclopentylamine.
ESI mass spectrum: [M+H].sup.+=222; Retention time HPLC: 0.72 min
(Z002.sub.--002).
8b:
5-Bromo-1-cyclopentyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00040##
[0169] Preparation 8b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 8a.
ESI mass spectrum: [M+H].sup.+=300 (bromine isotope pattern);
Retention time HPLC: 0.90 min (Z002.sub.--002).
8c:
1-Cyclopentyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro--
pyridine-3-carboxylic acid
##STR00041##
[0171] Preparation 8c is prepared following the procedure for
preparation 4, substituting preparation 3c with preparation 8b and
3-(difluoromethyl)phenylboronic acid with
3-(trifluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=366; Retention time HPLC: 0.71 min
(Z003.sub.--001).
Preparation 9
1-Cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyrid-
ine-3-carboxylic acid
##STR00042##
[0173] Preparation 9 is prepared following the procedure for
preparation 4, substituting preparation 3c with preparation 8b. ESI
mass spectrum: [M+H].sup.+=348; Retention time HPLC: 0.61 min
(Z003.sub.--001).
Preparation 10
5-Bromo-1-ethyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide
##STR00043##
[0174] 10a:
1-Ethyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid
##STR00044##
[0176] Preparation 10a is prepared following the procedure for
preparation 3b, substituting isopropylamine with ethylamine. ESI
mass spectrum: [M+H].sup.+=182; Retention time HPLC: 0.63 min
(Z002.sub.--006).
10b:
5-Bromo-1-ethyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00045##
[0178] Preparation 10b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 10a.
ESI mass spectrum: [M+H].sup.+=260 (bromine isotope pattern);
Retention time HPLC: 0.89 min (Z002.sub.--007).
10c:
5-Bromo-1-ethyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide
##STR00046##
[0180] Preparation 10c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 10b.
ESI mass spectrum: [M+H].sup.+=427 (bromine isotope pattern);
Retention time HPLC: 0.77 min (Z003.sub.--001).
Preparation 11
(R)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide
##STR00047##
[0181] 11a:
(R)-1-sec-Butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00048##
[0183] Preparation 11a is prepared following the procedure for
preparation 3b, substituting isopropylamine with (R)-2-aminobutane.
ESI mass spectrum: [M+H].sup.+=210; Retention time HPLC: 0.86 min
(Z002.sub.--006).
11b:
(R)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxy-
lic acid
##STR00049##
[0185] Preparation 11b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 11a.
ESI mass spectrum: [M+H].sup.+=288 (bromine isotope pattern);
Retention time HPLC: 1.08 min (Z002.sub.--006).
11c:
(R)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxy-
lic acid 4-methanesulfonyl-benzylamide
##STR00050##
[0187] Preparation 11c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 11b.
ESI mass spectrum: [M+H].sup.+=455 (bromine isotope pattern);
Retention time HPLC: 0.93 min (Z018_S04).
Preparation 12
(S)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide
##STR00051##
[0188] 12a:
(S)-1-sec-Butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00052##
[0190] Preparation 12a is prepared following the procedure for
preparation 3b, substituting isopropylamine with (S)-2-aminobutane.
ESI mass spectrum: [M+H].sup.+=210; Retention time HPLC: 0.86 min
(Z002.sub.--006).
12b:
(S)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxy-
lic acid
##STR00053##
[0192] Preparation 12b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 12a.
ESI mass spectrum: [M+H].sup.+=288 (bromine isotope pattern);
Retention time HPLC: 1.08 min (Z002.sub.--006).
12c:
(S)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxy-
lic acid 4-methanesulfonyl-benzylamide
##STR00054##
[0194] Preparation 12c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 12b.
ESI mass spectrum: [M+H].sup.+=455 (bromine isotope pattern);
Retention time HPLC: 0.93 min (Z018_S04).
Preparation 13
5-Iodo-1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyli-
c acid 4-methanesulfonyl-benzylamide
##STR00055##
[0195] 13a:
1-(2-Methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00056##
[0197] Preparation 13a is prepared following the procedure for
preparation 3b, substituting isopropylamine with
2-methoxyethylamine. ESI mass spectrum: [M+H].sup.+=212; Retention
time HPLC: 0.65 min (Z002.sub.--005).
13b:
5-Iodo-1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid
##STR00057##
[0199] A solution
1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (150 mg, 0.71 mmol) and N-iodosuccinimide (200 mg, 0.89 mmol)
in TFA (1 mL) and dichloromethane (1 mL) is stirred for 5 days at
room temperature. The reaction mixture is diluted with water and
extracted with dichloromethane. The organic layer is evaporate
under reduced pressure. ESI mass spectrum: [M+H].sup.+=338;
Retention time HPLC: 0.95 min (Z002.sub.--005).
13c:
5-Iodo-1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid 4-methanesulfonyl-benzylamide
##STR00058##
[0201] Preparation 13c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 13b and
HTBU with TBTU as coupling reagent. ESI mass spectrum:
[M+H].sup.+=505; Retention time HPLC: 1.11 min
(Z002.sub.--005).
Preparation 14
5-Bromo-6-methyl-4-oxo-1-(tetrahydro-furan-3-yl)-1,4-dihydro-pyridine-3-ca-
rboxylic acid 4-methanesulfonyl-benzylamide
##STR00059##
[0202] 14a:
6-Methyl-4-oxo-1-(tetrahydro-furan-3-yl)-1,4-dihydro-pyridine-3-carboxyli-
c acid
##STR00060##
[0204] Preparation 14a is prepared following the procedure for
preparation 3b, substituting isopropylamine with
tetrahydrofuran-3-ylamine. ESI mass spectrum: [M+H].sup.+=224;
Retention time HPLC: 0.55 min (Z002.sub.--006).
14b:
5-Bromo-6-methyl-4-oxo-1-(tetrahydro-furan-3-yl)-1,4-dihydro-pyridine-
-3-carboxylic acid
##STR00061##
[0206] Preparation 14b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 14a.
ESI mass spectrum: [M+H].sup.+=302 (bromine isotope pattern);
Retention time HPLC: 0.71 min (Z018_S04).
14c:
5-Bromo-6-methyl-4-oxo-1-(tetrahydro-furan-3-yl)-1,4-dihydro-pyridine-
-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00062##
[0208] Preparation 14c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 14b.
ESI mass spectrum: [M+H].sup.+=469 (bromine isotope pattern);
Retention time HPLC: 0.82 min (Z018_S04).
Preparation 15
5-Bromo-1-(1-ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyli-
c acid 4-methanesulfonyl-benzylamide
##STR00063##
[0209] 15a:
1-(1-Ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00064##
[0211] Preparation 15a is prepared following the procedure for
preparation 3b, substituting isopropylamine with 3-aminopentane.
ESI mass spectrum: [M+H].sup.+=224; Retention time HPLC: 0.76 min
(Z018_S04).
15b:
5-Bromo-1-(1-ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid
##STR00065##
[0213] Preparation 15b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 15a.
ESI mass spectrum: [M+H].sup.+=302 (bromine isotope pattern);
Retention time HPLC: 0.91 min (Z018_S04).
15c:
5-Bromo-1-(1-ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid 4-methanesulfonyl-benzylamide
##STR00066##
[0215] Preparation 15c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 15b.
ESI mass spectrum: [M+H].sup.+=469 (bromine isotope pattern);
Retention time HPLC: 0.94 min (Z018_S04).
Preparation 17
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00067##
[0217] Preparation 17 is prepared following the procedure for
preparation 5, substituting 4-methylsulfonylbenzylamine
hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
ESI mass spectrum: [M+H].sup.+=442 (bromine isotope pattern);
Retention time HPLC: 0.66 min (Z011_S03).
Preparation 18
5-Bromo-1-cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00068##
[0219] Preparation 18 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 7b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=454 (bromine isotope pattern); Retention time HPLC:
1.14 min (Z002.sub.--006).
Preparation 19
(R)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00069##
[0221] Preparation 19 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 11b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=456 (bromine isotope pattern); Retention time HPLC:
0.87 min (Z018_S04).
Preparation 20
(S)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00070##
[0223] Preparation 20 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 12b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=456 (bromine isotope pattern); Retention time HPLC:
0.87 min (Z018_S04).
Preparation 21
5-Iodo-1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyli-
c acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00071##
[0225] Preparation 22 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 13b,
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine and HBTU with TBTU.
ESI mass spectrum: [M+H].sup.+=506; Retention time HPLC: 0.90 min
(Z003.sub.--003).
Preparation 22
5-Bromo-6-methyl-4-oxo-1-(tetrahydro-furan-3-yl)-1,4-dihydro-pyridine-3-ca-
rboxylic acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00072##
[0227] Preparation 22 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 14b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=470 (bromine isotope pattern); Retention time HPLC:
0.77 min (Z018_S04).
Preparation 23
5-Bromo-1-(1-ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyli-
c acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00073##
[0229] Preparation 23 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 15b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=470 (bromine isotope pattern); Retention time HPLC:
0.91 min (Z018_S04).
Preparation 24
5-Bromo-1-cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00074##
[0231] Preparation 24 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 7b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=381 (bromine isotope pattern); Retention time HPLC:
0.69 min (Z003.sub.--001).
Preparation 25
(R)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00075##
[0233] Preparation 25 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 11b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=383 (bromine isotope pattern); Retention time HPLC:
0.83 min (Z018_S04).
Preparation 26
(S)-5-Bromo-1-sec-butyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00076##
[0235] Preparation 26 is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 12b and
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=383 (bromine isotope pattern); Retention time HPLC:
0.83 min (Z018_S04).
Preparation 27
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfinyl-benzylamide
##STR00077##
[0237] Preparation 17 is prepared following the procedure for
preparation 5, substituting 4-methylsulfonylbenzylamine
hydrochloride with 4-methylsulfinylbenzylamine hydrochloride
(Array, A1176-1). ESI mass spectrum: [M+H].sup.+=425 (bromine
isotope pattern); Retention time HPLC: 0.74 min
(Z003.sub.--001).
Preparation 28
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-3-methyl-benzylamide
##STR00078##
[0239] Preparation 28 is prepared following the procedure for
preparation 5, substituting 4-methylsulfonylbenzylamine
hydrochloride with 4-methanesulfonyl-3-methyl-benzylamine
(FCHGROUP). ESI mass spectrum: [M+H].sup.+=455 (bromine isotope
pattern); Retention time HPLC: 0.74 min (Z011_S03).
Preparation 29
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-ami-
de
##STR00079##
[0241] Preparation 29 is prepared following the procedure for
preparation 5, substituting 4-methylsulfonylbenzylamine
hydrochloride with
C-(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[b]thiophen-5-yl)-methyla-
mine (FCHGROUP). ESI mass spectrum: [M+H].sup.+=453 (bromine
isotope pattern); Retention time HPLC: 0.71 min (Z011_S03).
Example 1.1
1-Ethyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-
-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00080##
[0243] A mixture of
6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid 4-methanesulfonyl-benzylamide (preparation 1, 100 mg,
0.215 mmol), K.sub.2CO.sub.3 (48 mg, 0.344 mmol) and iodoethane (20
.mu.L, 0.250 mmol) in DMF (1 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: 52 mg (49% of theory); ESI mass spectrum:
[M+H].sup.+=493; Retention time HPLC: 1.03 min
(Z003.sub.--001).
[0244] The following Examples are prepared as described for Example
1.1, employing the corresponding alkylating agents instead of
iodoethane, respectively.
##STR00081##
TABLE-US-00002 Ex- MS Retention am- Alkylating [M + time HPLC/ ple
agent R.sup.a H].sup.+ Method 1.2 ##STR00082## ##STR00083## 507
1.06 min Z003_001 1.3 ##STR00084## ##STR00085## 507 1.09 min
Z003_001 1.4 ##STR00086## ##STR00087## 519 1.09 min Z003_001 1.5
##STR00088## ##STR00089## 521 1.13 min Z003_001 1.6 ##STR00090##
##STR00091## 549 1.03 min Z003_001 1.7 ##STR00092## ##STR00093##
555 1.04 min Z003_001
[0245] The following examples are prepared as described for Example
1.1, substituting preparation 1 with preparation 2 and employing
the corresponding alkylating agents instead of iodoethane,
respectively.
##STR00094##
TABLE-US-00003 Ex- MS Retention am- Alkylating [M + time HPLC/ ple
agent R.sup.b H].sup.+ Method 2.1 ##STR00095## ##STR00096## 494
1.00 min Z003_001 2.2 ##STR00097## ##STR00098## 508 1.05 min
Z003_001 2.3 ##STR00099## ##STR00100## 522 1.09 min Z003_001 2.4
##STR00101## ##STR00102## 550 0.99 min Z003_001
Example 3.1
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00103##
[0247] A solution of
1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid (preparation 3, 65 mg, 0.192 mmol), TBTU (75
mg, 0.232 mmol), N-methylmorpholine (42 .mu.L, 0.383 mmol) in DMF
(1 mL) is stirred for 15 min at room temperature.
C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine (24 mg, 0.211 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 (Sunfire, gradient of acetonitrile in water,
0.1% TFA, 60.degree. C.). Yield: 6 mg (7% of theory); ESI mass
spectrum: [M+H].sup.+=435; Retention time HPLC: 0.86 min
(Z018_S04).
[0248] The following examples are prepared as described for Example
3.1, substituting N-methylmorpholine with triethylamine and
employing the appropriate amines, respectively.
##STR00104##
TABLE-US-00004 Ex MS Retention am- [M + time HPLC/ ple
R.sup.cR.sup.dN-- H].sup.+ Method 3.2 ##STR00105## 430 0.69 min
004_CA05 3.3 ##STR00106## 431 0.65 min 004_CA05 3.4 ##STR00107##
433 0.68 min 004_CA05 3.5 ##STR00108## 454 0.80 min 004_CA05 3.6
##STR00109## 507 0.74 min 004_CA05 3.7 ##STR00110## 508 0.66 min
004_CA05 3.8 ##STR00111## 513 0.71 min 004_CA05 3.9 ##STR00112##
526 0.75 min 004_CA05
[0249] The following examples are prepared as described for Example
3.1, substituting preparation 3 with preparation 4, substituting
N-methylmorpholine with triethylamine and employing the appropriate
amines, respectively.
##STR00113##
TABLE-US-00005 Ex- MS Retention am- [M + time HPLC/ ple
R.sup.eR.sup.fN-- H].sup.+ Method 4.1 ##STR00114## 413 0.87 min
002_CA04 4.2 ##STR00115## 415 0.91 min 002_CA04 4.3 ##STR00116##
417 0.90 min 002_CA04 4.4 ##STR00117## 428 0.86 min 002_CA04 4.5
##STR00118## 436 1.10 min 002_CA04 4.6 ##STR00119## 451 0.96 min
002_CA04 4.7 ##STR00120## 465 1.05 min 002_CA04 4.8 ##STR00121##
473 0.93 min 002_CA04 4.9 ##STR00122## 489 1.02 min 002_CA04 4.10
##STR00123## 490 0.75 min 002_CA04 4.11 ##STR00124## 491 1.00 min
002_CA04 4.12 ##STR00125## 495 0.97 min 002_CA04 4.13 ##STR00126##
508 1.01 min 002_CA04 4.14 ##STR00127## 489 0.93 min Z003_001
Example 5.1
1-Isopropyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridiny-
l-5-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00128##
[0251] To a solution of
5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid 4-methanesulfonyl-benzylamide (preparation 5, 24 mg, 0.054
mmol), 2-(trifluoromethyl)pyridine-4-boronic acid (13 mg, 0.068
mmol), 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(5 mg, 0.007 mmol) in acetonitrile (0.15 mL) is added 2 M aqueous
K.sub.2CO.sub.3 solution (0.055 mL, 0.11 mmol). After stirring for
18 h at 75.degree. C., the reaction mixture is filtered and
purified by preparative reversed-phase HPLC (XBridge, gradient of
methanol in water, 0.3% NH.sub.4OH, 60.degree. C.). Yield: 4 mg
(15% of theory); ESI mass spectrum: [M+H].sup.+=508; Retention time
HPLC: 0.88 min (Z003.sub.--001).
[0252] The following examples are prepared as described for Example
5.1, employing the appropriate aryl- or heteroarylboronic
acids.
##STR00129##
TABLE-US-00006 MS Retention time Example R.sup.g [M + H].sup.+
HPLC/Method 5.2 ##STR00130## 525 1.01 min Z012_S04 5.3 ##STR00131##
541 0.93 min Z011_S03 5.4 ##STR00132## 507 0.96 min Z012_S04 5.5
##STR00133## 508 0.90 min Z003_001
Example 6
1-Cyclopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyri-
dine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00134##
[0254] Example 6 is prepared as described for Example 3.1,
substituting preparation 3 with preparation 6 and substituting
C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with
4-methylsulfonylbenzylamine hydrochloride. ESI mass spectrum:
[M+H].sup.+=505; Retention time HPLC: 0.60 min
(Z003.sub.--001).
Example 7
1-Cyclobutyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00135##
[0256] Example 7 is prepared as described for Example 9,
substituting preparation 3 with preparation 7 and substituting
C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with
4-methylsulfonylbenzylamine hydrochloride. ESI mass spectrum:
[M+H].sup.+=519; Retention time HPLC: 1.06 min
(Z003.sub.--001).
Example 8.1
1-Cyclopentyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyri-
dine-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00136##
[0258] Example 8.1 is prepared following the procedure for Example
3.1, substituting preparation 3 with preparation 8. ESI mass
spectrum: [M+H].sup.+=461; Retention time HPLC: 1.03 min
(Z003.sub.--001).
Example 8.2
1-Cyclopentyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyri-
dine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00137##
[0260] Example 9.2 is prepared as described for Example 3.1,
substituting preparation 3 with preparation 8 and substituting
C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with
4-methylsulfonylbenzylamine hydrochloride. ESI mass spectrum:
[M+H].sup.+=533; Retention time HPLC: 1.08 min
(Z003.sub.--001).
Example 9.1
1-Cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyrid-
ine-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00138##
[0262] A solution of
1-cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyri-
dine-3-carboxylic acid (preparation 9, 116 mg, 0.334 mmol), HBTU
(140 mg, 0.369 mmol), DIPEA (116 .mu.L, 0.668 mmol) in DMF (1 mL)
is stirred for 15 min at room temperature.
C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine (46 mg, 0.407 mmol)
is added and the reaction mixture is stirred for 72 h at room
temperature. 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: 67 mg (45% of theory); ESI mass
spectrum: [M+M].sup.+=443; Retention time HPLC: 0.98 min
(Z003.sub.--001).
Example 9.2
1-Cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyrid-
ine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00139##
[0264] Example 9.2 is prepared as described for Example 3.1,
substituting preparation 3 with preparation 9 and substituting
C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with
4-methylsulfonylbenzylamine hydrochloride. ESI mass spectrum:
[M+H].sup.+=515; Retention time HPLC: 1.02 min
(Z003.sub.--001).
Example 10
5-(3-Difluoromethyl-phenyl)-1-ethyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3--
carboxylic acid 4-methanesulfonyl-benzylamide
##STR00140##
[0266] Example 10 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 10 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=475; Retention time HPLC: 0.95 min
(Z003.sub.--001).
Example 11.1
(R)-1-sec-Butyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00141##
[0268] Example 11.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 11 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=503; Retention time HPLC: 0.96 min
(Z003.sub.--001).
Example 11.2
(R)-1-sec-Butyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyri-
dinyl-5-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00142##
[0270] Example 11.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 11 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=522; Retention time HPLC: 0.92 min
(Z003.sub.--001).
Example 12.1
(S)-1-sec-Butyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-py-
ridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00143##
[0272] Example 12.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 12. ESI mass
spectrum: [M+H].sup.+=521; Retention time HPLC: 1.05 min
(Z003.sub.--001).
Example 12.2
(S)-1-sec-Butyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00144##
[0274] Example 12.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 12 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=503; Retention time HPLC: 0.96 min
(Z003.sub.--001).
Example 12.3
(S)-1-sec-Butyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyri-
dinyl-5-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00145##
[0276] Example 12.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 12 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=522; Retention time HPLC: 0.92 min
(Z003.sub.--001).
Example 13
1-(2-Methoxy-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00146##
[0278] Example 13 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 13. ESI mass
spectrum: [M+H].sup.+=523; Retention time HPLC: 1.18 min
(Z003.sub.--003).
Example 14.1
6-Methyl-4-oxo-1-(tetrahydro-furan-3-yl)-5-(3-trifluoromethyl-phenyl)-1,4--
dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00147##
[0280] Example 14.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 14. ESI mass
spectrum: [M+H].sup.+=517; Retention time HPLC: 0.77 min
(Z011_S03).
Example 14.2
5-(3-Difluoromethyl-phenyl)-6-methyl-4-oxo-1-(tetrahydro-furan-3-yl)-1,4-d-
ihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00148##
[0282] Example 14.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 14 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=535; Retention time HPLC: 0.94 min
(Z003.sub.--001).
Example 15.1
1-(1-Ethyl-propyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-
-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00149##
[0284] Example 15.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 15. ESI mass
spectrum: [M+H].sup.+=535; Retention time HPLC: 1.11 min
(Z018_S04).
Example 15.2
5-(3-Difluoromethyl-phenyl)-1-(1-ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro--
pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00150##
[0286] Example 15.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 15 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=517; Retention time HPLC: 1.06 min (Z018_S04).
Example 15.3
1-(1-Ethyl-propyl)-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bip-
yridinyl-5-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00151##
[0288] Example 15.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 15 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=536; Retention time HPLC: 1.02 min (Z018_S04).
Example 16
1-(2-Methoxy-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid
(5-methanesulfonyl-1-oxy-pyridin-2-ylmethyl)-amide
##STR00152##
[0290] To a solution of
1-(2-methoxy-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihyd-
ro-pyridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide (Example 21, 40 mg,
0.076 mmol) in dichloromethane (1 mL) is added
3-chloroperoxybenzoic acid (MCPBA, 88 mg, 0.357 mmol). After
stiffing for 1 day 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
(37% of theory); ESI mass spectrum: [M+].sup.+=540; Retention time
HPLC: 1.08 min (Z003.sub.--003).
Example 17.1
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00153##
[0292] Example 17.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 17. ESI mass
spectrum: [M+H].sup.+=508; Retention time HPLC: 1.03 min
(Z003.sub.--001).
Example 17.2
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00154##
[0294] Example 17.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 17 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=490; Retention time HPLC: 0.86 min
(Z003.sub.--001).
Example 17.3
1-Isopropyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridiny-
l-5-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00155##
[0296] Example 17.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 17 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=509; Retention time HPLC: 0.81 min
(Z003.sub.--001).
Example 18.1
1-Cyclobutyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00156##
[0298] Example 18.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 18. ESI mass
spectrum: [M+H].sup.+=520; Retention time HPLC: 1.06 min
(Z003.sub.--001).
Example 18.2
1-Cyclobutyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00157##
[0300] Example 18.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 18 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=502; Retention time HPLC: 0.91 min
(Z003.sub.--001).
Example 19.1
(R)-1-sec-Butyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-py-
ridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00158##
[0302] Example 19.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 19. ESI mass
spectrum: [M+H].sup.+=522; Retention time HPLC: 1.01 min
(Z003.sub.--001).
Example 19.2
(R)-1-sec-Butyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00159##
[0304] Example 19.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 19 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=504; Retention time HPLC: 0.91 min
(Z003.sub.--001).
Example 19.3
(R)-1-sec-Butyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyri-
dinyl-5-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00160##
[0306] Example 19.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 19 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=523; Retention time HPLC: 0.87 min
(Z003.sub.--001).
Example 20.1
(S)-1-sec-Butyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-py-
ridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00161##
[0308] Example 20.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 20. ESI mass
spectrum: [M+H].sup.+=522; Retention time HPLC: 1.01 min
(Z003.sub.--001).
Example 20.2
(S)-1-sec-Butyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00162##
[0310] Example 20.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 20 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=504; Retention time HPLC: 0.92 min
(Z002.sub.--006).
Example 20.3
(S)-1-sec-Butyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyri-
dinyl-5-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00163##
[0312] Example 20.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 20 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=523; Retention time HPLC: 0.87 min
(Z003.sub.--001).
Example 21
1-(2-Methoxy-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00164##
[0314] Example 21 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 21. ESI mass
spectrum: [M+H].sup.+=524; Retention time HPLC: 1.30 min
(Z002.sub.--005).
Example 22
6-Methyl-4-oxo-1-(tetrahydro-furan-3-yl)-5-(3-trifluoromethyl-phenyl)-1,4--
dihydro-pyridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00165##
[0316] Example 22 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 22. ESI mass
spectrum: [M+H].sup.+=518; Retention time HPLC: 0.74 min
(Z011_S03).
Example 23.1
1-(1-Ethyl-propyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-
-pyridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00166##
[0318] Example 23.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 23. ESI mass
spectrum: [M+H].sup.+=536; Retention time HPLC: 1.00 min
(Z018_S04).
Example 23.2
5-(3-Difluoromethyl-phenyl)-1-(1-ethyl-propyl)-6-methyl-4-oxo-1,4-dihydro--
pyridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00167##
[0320] Example 23.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 23 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=518; Retention time HPLC: 1.01 min (Z018_S04).
Example 23.3
1-(1-Ethyl-propyl)-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bip-
yridinyl-5-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00168##
[0322] Example 23.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 23 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=537; Retention time HPLC: 0.98 min (Z018_S04).
Example 24.1
1-Cyclobutyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00169##
[0324] To a solution of
5-bromo-1-cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide (preparation 24,
44 mg, 0.115 mmol), 3-(trifluoromethyl)phenyl-boronic acid (26 mg,
0.137 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg,
0.018 mmol) in acetonitrile (0.5 mL) is added 2 M aqueous
K.sub.2CO.sub.3 solution (0.10 mL, 0.20 mmol). After stirring for
18 h at 75.degree. C., the reaction mixture is filtered and
purified by preparative reversed-phase HPLC (XBridge, gradient of
methanol in water, 0.3% NH.sub.4OH, 60.degree. C.). Yield: 40 mg
(78% of theory); ESI mass spectrum: [M+H].sup.+=447; Retention time
HPLC: 1.09 min (Z003.sub.--001).
Example 24.2
1-Cyclobutyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00170##
[0326] Example 24.2 is prepared following the procedure for Example
24.1, substituting 3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=429; Retention time HPLC: 0.89 min
(Z003.sub.--001).
Example 25.1
(R)-1-sec-Butyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-py-
ridine-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00171##
[0328] Example 25.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 25. ESI mass
spectrum: [M+H].sup.+=449; Retention time HPLC: 1.03 min
(Z003.sub.--001).
Example 25.2
(R)-1-sec-Butyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00172##
[0330] Example 25.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 25 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=431; Retention time HPLC: 0.90 min
(Z003.sub.--001).
Example 26
(S)-1-sec-Butyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid
(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide
##STR00173##
[0332] Example 26 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 26 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=431; Retention time HPLC: 0.90 min
(Z003.sub.--001).
Example 27.1
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-methanesulfinyl-benzylamide
##STR00174##
[0334] Example 27.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 27. ESI mass
spectrum: [M+H].sup.+=491; Retention time HPLC: 1.41 min
(Z002.sub.--006).
Example 27.2
1-Isopropyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridiny-
l-5-carboxylic acid 4-methanesulfinyl-benzylamide
##STR00175##
[0336] Example 27.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 27 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=492; Retention time HPLC: 1.28 min
(Z002.sub.--006).
Example 28.1
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-methanesulfonyl-3-methyl-benzylamide
##STR00176##
[0338] Example 28.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 28. ESI mass
spectrum: [M+H].sup.+=521; Retention time HPLC: 0.90 min
(Z011_S03).
Example 28.2
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid 4-methanesulfonyl-3-methyl-benzylamide
##STR00177##
[0340] Example 28.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 28 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=503; Retention time HPLC: 0.84 min (Z011_S03).
Example 28.3
1-Isopropyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridiny-
l-5-carboxylic acid 4-methanesulfonyl-3-methyl-benzylamide
##STR00178##
[0342] Example 28.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 28 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=522; Retention time HPLC: 0.81 min (Z011_S03).
Example 29.1
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-ami-
de
##STR00179##
[0344] Example 29.1 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 29. ESI mass
spectrum: [M+H].sup.+=519; Retention time HPLC: 0.87 min
(Z011_S03).
Example 29.2
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid
(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-ami-
de
##STR00180##
[0346] Example 29.2 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 29 and
3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=501; Retention time HPLC: 0.81 min (Z011_S03).
Example 29.3
1-Isopropyl-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4]bipyridinyl-
-5-carboxylic acid
(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-ami-
de
##STR00181##
[0348] Example 29.3 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 29 and
3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=520; Retention time HPLC: 0.79 min (Z011_S03).
Example 30.1
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-ethanesulfonyl-benzylamide
##STR00182##
[0349] Example 30.2
6-Ethyl-1-isopropyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridin-
e-3-carboxylic acid 4-ethanesulfonyl-benzylamide
##STR00183##
[0351] To a solution of
1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid 4-methanesulfonyl-benzylamide (Example 1.2,
120 mg, 0.237 mmol) in THF (5 mL) is added at -65.degree. C.
n-butyl lithium (0.37 mL of 1.6 M solution in hexanes, 0.592 mmol).
After stirring for 1 h at -65.degree. C., iodomethane (22 .mu.L,
0.355 mmol) is added and the reaction mixture is stirred for 2 h at
-65.degree. C. After stirring overnight at room temperature, the
reaction mixture is quenched with water and extracted several times
with ethyl acetate. The combined organic layer is dried over
Na.sub.2SO.sub.4, evaporated under reduced pressure and the
purified by preparative reversed-phase HPLC (XBridge, gradient of
acetonitrile in water, 0.1% TFA, 60.degree. C.) to yield 10 mg of
Example 30.1; ESI mass spectrum: [M+H].sup.+=521; Retention time
HPLC: 1.03 min (Z012_S04); 6 mg of Example 30.2; ESI mass spectrum:
[M+H].sup.+=535; Retention time HPLC: 1.06 min (Z012_S04).
Example 27.1A and Example 27.1B
Enantiomers of Example 27.1
[0352] 147 mg of racemic example 27.1 are separated by chiral HPLC
(Daicel IB, 250 mm.times.20 mm, 10% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C.).
[0353] Early eluting enantiomer (Example 27.1A): Retention time
chiral HPLC=7.36 min (Daicel Chiralpak.RTM. ODH, 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.+=491. Yield: 33 mg
[0354] Late eluting enantiomer (Example 27.1B): Retention time
chiral HPLC=7.92 min (Daicel Chiralpak.RTM. ODH, 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.+=491. Yield: 32 mg
Example 31
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-cyclopropanesulfonyl-benzylamide
##STR00184##
[0355] 31a: 4-Cyclopropylsulfanyl-benzamide
##STR00185##
[0357] Thionylchloride (342 .mu.L, 4.7 mmol) is added to a solution
of 4-cyclopropylsulfanyl-benzoic acid (prepared as described in
WO07003960, 190 mg, 0.98 mmol) in dichloromethane (1.9 mL). The
mixture is heated at reflux for 30 min and concentrated under
reduced pressure. The residue is treated with toluene, and all
volatiles are evaporated. The residue is dissolved in chloroform
(1.9 mL) and treated with concentrated aqueous ammonia (770 .mu.L,
9.8 mmol). The mixture is stirred at room temperature for 1 h and
then extracted with water. The organic layer is dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Yield:
137 mg (72% of theory); ESI mass spectrum: [M+H].sup.+=194;
Retention time HPLC: 0.45 min (X011_S03).
31b: 4-Cyclopropylsulfanyl-benzylamine
##STR00186##
[0359] A solution of 4-cyclopropylsulfanyl-benzamide (preparation
31a, 137 mg, 0.71 mmol) in dry tetrahydrofuran (1.0 mL) is added at
0.degree. C. to a solution of lithium aluminium hydride in
tetrahydrofuran (1 M, 2.1 mL, 2.1 mmol). The mixture is stirred at
0.degree. C. for 1 h and heated at reflux for 1 h. The mixture is
cooled at room temperature and stirred for 1.5 h. Water is added,
and the mixture is extracted twice with dichloromethane. The
combined organic layers are dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Yield: 75 mg (60% of theory);
ESI mass spectrum: [M+H].sup.+=180; Retention time HPLC: 0.51 min
(X011_S03).
31c
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-py-
ridine-3-carboxylic acid 4-cyclopropylsulfanyl-benzylamide
##STR00187##
[0361] Preparation 31c is prepared as described for Example 3.1,
substituting N-methylmorpholine with triethylamine and substituting
C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine with
4-cyclopropanesulfonyl-benzylamine (preparation 31b). ESI mass
spectrum: [M+H].sup.+=501; Retention time HPLC: 0.77 min
(X012_S01).
Example 31
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-cyclopropanesulfonyl-benzylamide
##STR00188##
[0363] 3-Chloroperoxybenzoic acid (45 mg, 77%, 0.201 mmol) is added
to a solution of preparation 31c (50 mg, 0.100 mmol) in
dichloromethane (1 mL). The reaction mixture is stirred for 1 h at
room temperature. The reaction mixture is quenched with aqueous
sodium thiosulfate solution and extracted with dichloromethane.
After drying of the organic phase, the volatiles are removed 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: 31 mg (59% of theory);
ESI mass spectrum: [M+H].sup.+=533; Retention time HPLC: 0.89 min
(005_CA01).
Example 32
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 3-fluoro-4-methanesulfonyl-benzylamide
##STR00189##
[0364] 32a:
2-(3-Fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione
##STR00190##
[0366] A mixture of 3-fluoro-4-methylsulfanyl-benzonitrile (6.00 g,
34.1 mmol), Raney-Nickel (100 mg) and concentrated aqueous ammonia
(30 mL) in methanol (300 mL) is treated with hydrogen (3.4 bar) at
room temperature for 3 h. The mixture is filtered through a pad of
silica gel, and the filtrate is concentrated under reduced
pressure. The residue is dissolved in toluene (250 mL), and the
mixture is treated with phthalic anhydride (4.0 g, 26.3 mmol) and
triethylamine (0.98 g, 9.50 mmol) and heated at reflux over night.
All volatiles are removed, and the residue is recrystallized from
ethanol. Yield: 4.50 g (43% of theory). ESI mass spectrum:
[M+H].sup.+=302; Retention time HPLC: 0.67 min (X012_S01).
32b: 3-Fluoro-4-methanesulfonyl-benzylamine
##STR00191##
[0368] 3-Chloroperoxybenzoic acid (77%, 8.3 g, 37.2 mmol) is added
to a mixture of
2-(3-fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione
(preparation 32a, 6.00 g, 18.9 mmol) and dichloromethane (580 mL).
After 1 h saturated aqueous sodium thiosulfate solution is added,
and the mixture is extracted with dichloromethane. The organic
layer is dried under reduced pressure, and the residue is purified
by flash chromatography on silica (cyclohexane/ethyl acetate
5:1).
[0369] The purified intermediate
2-(3-fluoro-4-methylsulfonyl-benzyl)-isoindole-1,3-dione (5.50 g,
15.6 mmol) is dissolved in a mixture of methanol (250 mL) and
dichloromethane (250 mL). Hydrazine hydrate (4.6 g, 78.4 mmol) is
added, and the mixture is stirred at 60.degree. C. for 3 h. The
mixture is filtered, and the filtrate is treated with water. The
mixture is extracted with ethyl acetate, and the organic layer is
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue is purified by preparative reversed-phase
HPLC (Luna C18 250*50 mm, gradient of acetonitrile in water, 0.1%
TFA). Yield: 3.1 g (81% of theory); ESI mass spectrum:
[M+H].sup.+=204; Retention time HPLC: 0.17 min (X012_S01).
Example 32
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 3-fluoro-4-methanesulfonyl-benzylamide
##STR00192##
[0371] To a solution of
1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrid-
ine-3-carboxylic acid (preparation 3, 60 mg, 0.177 mmol),
preparation 32b (72 mg, 0.354 mmol), N-methylmorpholine (0.10 mL,
0.910 mmol) in dichloromethane (1 mL) is added at 0.degree. C.
1-propanephosphonic acid cyclic anhydride in ethyl acetate (0.31
mL, 50%, 0.53 mmol). The reaction mixture is stirred for 18 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: 24 mg (26% of theory); ESI mass
spectrum: [M+H].sup.+=525; Retention time HPLC: 0.86 min
(005_CA01).
Example 33
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid 3-fluoro-4-methanesulfonyl-benzylamide
##STR00193##
[0373] Example 33 is prepared as described for Example 32,
substituting preparation 3 with preparation 4. ESI mass spectrum:
[M+H].sup.+=507; Retention time HPLC: 0.54 min (001_CA07).
Example 34
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 2-fluoro-4-methanesulfonyl-benzylamide
##STR00194##
[0374] 34a: 2-Fluoro-4-methylsulfanyl-benzylamine
##STR00195##
[0376] A mixture of 2-fluoro-4-methylsulfanyl-benzonitrile (8.0 g,
45.5 mmol), Raney-Nickel (20.0 g) and concentrated aqueous ammonia
(300 mL) in methanol (3.0 L) is treated with hydrogen (3.4 bar) at
room temperature and stirred over night. The mixture is filtered
through a pad of silica gel, and the filtrate is concentrated under
reduced pressure. Yield: 6.3 g (81% of theory); ESI mass spectrum:
[M+H--NH.sub.3].sup.+=155; Retention time HPLC: 1.38 min
(0-30AB).
34b: 2-(2-Fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione
##STR00196##
[0378] A mixture of 2-fluoro-4-methylsulfanyl-benzylamine
(preparation 34a, 10.0 g, 52.6 mmol) and phthalic anhydride (7.94
g, 52.6 mmol) in toluene (510 mL) is heated at reflux over night.
All volatiles are removed under reduced pressure, and the residue
is recrystallized from hot ethanol. Yield: 9.2 g (55% of theory);
ESI mass spectrum: [M+Na].sup.+=302; Retention time HPLC: 0.67 min
(X012_S01).
34c: 2-Fluoro-4-methanesulfonyl-benzylamine
##STR00197##
[0380] Preparation 34c is prepared in analogy to preparation 32b,
using 2-(2-fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione
(preparation 34b) as starting material. ESI mass spectrum:
[M+H].sup.+=204; Retention time HPLC: 1.40 min (0-30HPLC).
Example 34
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 2-fluoro-4-methanesulfonyl-benzylamide
##STR00198##
[0382] Example 34 is prepared as described for Example 32,
substituting preparation 32b with preparation 34c. ESI mass
spectrum: [M+H].sup.+=525; Retention time HPLC: 0.86 min
(005_CA01).
Example 35
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid 2-fluoro-4-methanesulfonyl-benzylamide
##STR00199##
[0384] Example 35 is prepared as described for Example 32,
substituting preparation 32b with preparation 34c and substituting
preparation 3 with preparation 4. ESI mass spectrum:
[M+H].sup.+=507; Retention time HPLC: 0.53 min (002_CA07).
Example 36
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-methanesulfonyl-2-methyl-benzylamide
##STR00200##
[0385] 36a:
2-(4-Methanesulfanyl-2-methyl-benzyl)-isoindole-1,3-dione
##STR00201##
[0387] A mixture of 2-methyl-4-methylsulfanyl-benzonitrile
(prepared as described in WO09126863, 2.3 g, 14 mmol), Raney-Nickel
(1.0 g) and concentrated aqueous ammonia (50 mL) in methanol (200
mL) is treated with hydrogen (3.4 bar) at room temperature over
night. The mixture is filtered, and all volatiles are removed under
reduced pressure. The residue (2.3 g, 11.0 mmol based on 80%
purity) is mixed with phthalic anhydride (1.66 g, 11.0 mmol),
triethylamine (450 mg, 4.40 mmol) and toluene (100 mL), and the
mixture is heated at 90.degree. C. over night. All volatiles were
removed under reduced pressure, and the residue is recrystallized
from hot ethanol. Yield: 1.30 g (31% of theory); ESI mass spectrum:
[M+H].sup.+=298; Retention time HPLC: 0.70 min (X011_S03).
36b: 4-Methanesulfonyl-2-methyl-benzylamine
##STR00202##
[0389] Preparation 36b is prepared in analogy to preparation 32b,
using 2-(4-methanesulfanyl-2-methyl-benzyl)-isoindole-1,3-dione
(preparation 36a) as starting material. ESI mass spectrum:
[M+H].sup.+=200; Retention time HPLC: 2.12 min (CD00).
Example 36
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-methanesulfonyl-2-methyl-benzylamide
##STR00203##
[0391] Example 36 is prepared as described for Example 32,
substituting preparation 32b with preparation 36b. ESI mass
spectrum: [M+H].sup.+=521; Retention time HPLC: 0.86 min
(005_CA01).
Example 37
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid 4-methanesulfonyl-2-methyl-benzylamide
##STR00204##
[0393] Example 37 is prepared as described for Example 32,
substituting preparation 32b with preparation 36b and substituting
preparation 3 with preparation 4. ESI mass spectrum:
[M+H].sup.+=503; Retention time HPLC: 0.54 min (001_CA07).
Example 38
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-imidazo[2,1-b]thiazol-6-ylmethyl-
)-amide
##STR00205##
[0394] 38a
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dih-
ydro-pyridine-3-carboxylic acid
(2,3-dihydro-imidazol-[2,1-b]thiazol-6-ylmethyl)-amide
##STR00206##
[0396] Preparation 38a is prepared as described for Preparation 5,
substituting preparation 3c with preparation 3 and substituting
4-methylsulfonylbenzylamine hydrochloride with
5,7-dihydroimidazo[1,2-C]thiazol-2-ylmethanamine (Chembridge). ESI
mass spectrum: [M+H].sup.+=477; Retention time HPLC: 0.59 min
(005_CA01).
Example 38
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(1,1-dioxo-2,3-dihydro-1H-1.lamda..sup.6-imidazo[2,1-b]thiazol-6-ylmethyl-
)-amide
##STR00207##
[0398] 3-Chloroperoxybenzoic acid (26 mg, 0.15 mmol) is added to a
solution of preparation 38a (33 mg, 0.069 mmol) in dichloromethane
(3 mL). The reaction mixture is stirred for 6 h at room
temperature. The volatiles are removed under reduced pressure and
the remaining residue is purified by preparative reversed-phase
HPLC. Yield: 6 mg (17% of theory); ESI mass spectrum:
[M+H].sup.+=509; Retention time HPLC: 0.96 min (Z018_S04).
Example 39
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(5-methanesulfonyl-thiophen-2-ylmethyl)-amide
##STR00208##
[0399] 39a
5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carbo-
xylic acid (5-methanesulfonyl-thiophen-2-ylmethyl)-amide
##STR00209##
[0400] Preparation 39a is prepared following the procedure for
preparation 5, substituting 4-methylsulfonylbenzylamine
hydrochloride with (5-methanesulfonylthiophen-2-yl)methanamine
hydrochloride (Enamine). ESI mass spectrum: [+H]+=447 (bromine
isotope pattern); Retention time HPLC: 0.71 min (Z011_S03).
Example 39
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(5-methanesulfonyl-thiophen-2-ylmethyl)-amide
##STR00210##
[0402] Example 39 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 39a. ESI mass
spectrum: [M+H].sup.+=513; Retention time HPLC: 0.89 min
(Z011_S03).
Example 40
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid
(5-methanesulfonyl-thiophen-2-ylmethyl)-amide
##STR00211##
[0404] Example 40 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 39a and
replacing 3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=495; Retention time HPLC: 0.82 min (Z011_S03).
Example 41
(S)-1-(2-Methoxy-1-methyl-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-pheny-
l)-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00212##
[0405] 41a
(S)-1-(2-Methoxy-1-methyl-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid
##STR00213##
[0406] Preparation 41a is prepared following the procedure for
preparation 3b, substituting isopropylamine with
(S)-1-methoxy-2-propylamine. ESI mass spectrum: [M+H].sup.+=226;
Retention time HPLC: 0.65 min (Z018_S04).
41b
(S)-5-Bromo-1-(2-methoxy-1-methyl-ethyl)-6-methyl-4-oxo-1,4-dihydro-py-
ridine-3-carboxylic acid
##STR00214##
[0408] Preparation 41b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 41a.
ESI mass spectrum: [M+H].sup.+=304 (bromine isotope pattern);
Retention time HPLC: 0.81 min (Z018_S04).
41c
(S)-5-Bromo-1-(2-methoxy-1-methyl-ethyl)-6-methyl-4-oxo-1,4-dihydro-py-
ridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00215##
[0410] Preparation 41c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 41b.
ESI mass spectrum: [M+H].sup.+=471 (bromine isotope pattern);
Retention time HPLC: 0.88 min (Z018_S04).
Example 41
(S)-1-(2-Methoxy-1-methyl-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-pheny-
l)-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00216##
[0412] Example 41 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 41c. ESI mass
spectrum: [M+H].sup.+=537; Retention time HPLC: 1.02 min
(Z018_S04).
Example 42
(S)-5-(3-Difluoromethyl-phenyl)-1-(2-methoxy-1-methyl-ethyl)-6-methyl-4-ox-
o-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00217##
[0414] Example 42 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 41c and
replacing 3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=519; Retention time HPLC: 0.97 min (Z018_S04).
Example 43
(R)-1-(2-Methoxy-1-methyl-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-pheny-
l)-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00218##
[0415] 43a
(R)-1-(2-Methoxy-1-methyl-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyr-
idine-3-carboxylic acid
##STR00219##
[0417] Preparation 43a is prepared following the procedure for
preparation 3b, substituting isopropylamine with
(R)-1-methoxy-2-propylamine. ESI mass spectrum: [M+H].sup.+=226;
Retention time HPLC: 0.65 min (Z018_S04).
43b
(R)-5-Bromo-1-(2-methoxy-1-methyl-ethyl)-6-methyl-4-oxo-1,4-dihydro-py-
ridine-3-carboxylic acid
##STR00220##
[0419] Preparation 43b is prepared following the procedure for
preparation 3c, substituting preparation 3b with preparation 43a.
ESI mass spectrum: [M+H].sup.+=304 (bromine isotope pattern);
Retention time HPLC: 0.81 min (Z018_S04).
43 c
(R)-5-Bromo-1-(2-methoxy-1-methyl-ethyl)-6-methyl-4-oxo-1,4-dihydro-p-
yridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00221##
[0421] Preparation 43c is prepared following the procedure for
preparation 5, substituting preparation 3c with preparation 43b.
ESI mass spectrum: [M+H].sup.+=471 (bromine isotope pattern);
Retention time HPLC: 0.88 min (Z018_S04).
Example 43
(R)-1-(2-Methoxy-1-methyl-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-pheny-
l)-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00222##
[0423] Example 43 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 43c. ESI mass
spectrum: [M+H].sup.+=537; Retention time HPLC: 1.04 min
(Z018_S04).
Example 44
(R)-5-(3-Difluoromethyl-phenyl)-1-(2-methoxy-1-methyl-ethyl)-6-methyl-4-ox-
o-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00223##
[0425] Example 44 is prepared following the procedure for Example
24.1, substituting preparation 24 with preparation 43c and
replacing 3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=519; Retention time HPLC: 0.97 min (Z018_S04).
Example 45
1-(2-Fluoro-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-
-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00224##
[0427] Example 45 is prepared as described for Example 1.1,
substituting iodoethane with 1-bromo-2-fluoroethane and
substituting DMF with NMP. ESI mass spectrum: [M+H].sup.+=511;
Retention time HPLC: 0.99 min (Z018_S04).
Example 46
1-(2,2-Difluoro-ethyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dih-
ydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00225##
[0429] Example 46 is prepared as described for Example 1.1,
substituting iodoethane with 2-bromo-1,1-difluoroethane and
substituting DMF with NMP. ESI mass spectrum: [M+H].sup.+=529;
Retention time HPLC: 0.86 min (Z011_S03).
Example 47
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-methanesulfonyl-2-methoxy-benzylamide
##STR00226##
[0431] Example 47 is prepared as described for Example 32,
substituting preparation 32b with
4-methanesulfonyl-2-methoxy-benzylamine (preparation described in
WO2006/67462). ESI mass spectrum: [M+H].sup.+=537; Retention time
HPLC: 1.03 min (Z017_S04).
Example 48
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(1,1-dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-amide
##STR00227##
[0432] 48a: Benzo[b]thiophen-5-ylmethyl-carbamic acid tert-butyl
ester
##STR00228##
[0434] Di-tert-butyl dicarbonate (3.88 g, 17.5 mmol) is added to a
solution of benzo[b]thiophen-5-ylmethanamine (prepared as described
in WO01068652, 2.00 g, 11.6 mmol) and triethylamine (1.78 g, 17.5
mmol) in dichloromethane (40 mL), and the mixture is stirred at
room temperature for 1 h. Water is added, and the mixture is
extracted three times with dichloromethane. The combined organic
layers are dried over Na.sub.2SO.sub.4, concentrated under reduced
pressure. The residue is crystallized from hot petroleum ether.
Yield: 1.26 g; ESI mass spectrum: [M-C.sub.4H.sub.8+H].sup.+=208;
Retention time HPLC: 0.84 min (5-95AB).
48b:
(1,1-Dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-carbamic
acid tert-butyl ester
##STR00229##
[0436] 3-Chloroperoxybenzoic acid (77%, 1.58 g, 7.1 mmol) is added
to a mixture of benzo[b]thiophen-5-ylmethyl-carbamic acid
tert-butyl ester (preparation 48a, 1.00 g, 3.60 mmol) in
dichloromethane, and the mixture is stirred at room temperature for
1 h. Saturated aqueous sodium thiosulfate solution is added, and
the mixture is extracted three times with dichloromethane. The
combined organic layers are dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue is purified by
flash chromatography on silica (petroleum gradient: ether/ethyl
acetate 4:1 to 2:1). Yield: 770 mg (72% of theory). ESI mass
spectrum: [M-C.sub.4H.sub.8+H].sup.+=240; Retention time HPLC: 0.72
min (5-95AB).
48c:
C-(1,1-Dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-5-yl)-methylamine
##STR00230##
[0438] A solution of hydrogen chloride in ethyl acetate (4.0 M, 20
mL, 80 mmol) is added to a solution of
(1,1-dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-carbamic
acid tert-butyl ester (preparation 48b, 800 mg, 2.10 mmol) in
dichloromethane (5 mL), and the mixture was stirred at room
temperature for 1 h. The mixture was filtered, and the precipitate
was washed twice with ethyl acetate. Yield: 480 mg (97% of theory);
ESI mass spectrum: [M+H].sup.+=196; Retention time HPLC: 0.13 min
(5-95AB).
Example 48
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid
(1,1-dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-amide
##STR00231##
[0440] Example 48 is prepared as described for Example 3.1,
substituting C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine with
preparation 48c and substituting N-methylmorpholine with
triethylamine. ESI mass spectrum: [M+H].sup.+=517; Retention time
HPLC: 0.85 min (005_CA01).
Example 49
1-Isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridi-
ne-3-carboxylic acid 4-methanesulfonyl-3-methoxy-benzylamide
##STR00232##
[0442] Example 49 is prepared as described for Example 32,
substituting preparation 32b with
4-methanesulfonyl-3-methoxy-benzylamine (preparation described in
WO2004/43924). ESI mass spectrum: [M+H].sup.+=537; Retention time
HPLC: 1.03 min (Z018_S04).
Example 50
5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid
(1,1-dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-5-ylmethyl)-amide1
##STR00233##
[0444] Example 50 is prepared as described for Example 32,
substituting preparation 3 with preparation 4 and substituting
preparation 32b with preparation 48c. ESI mass spectrum:
[M+H].sup.+=499; Retention time HPLC: 0.54 min (001_CA07).
EXAMPLES
[0445] 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
[0446] 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.
[0447] 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.
[0448] 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.
[0449] 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-00007 Example IC50 [nM] 1.1 33 1.2 12 1.3 28 1.4 59 1.5 30
1.6 77 1.7 37 10 29 11.1 8 11.2 35 12.1 9 12.2 12 12.3 54 13 42
14.1 20 14.2 27 15.1 8 15.2 8 15.3 24 16 63 17.1 73 17.2 15 17.3 77
18.1 32 18.2 35 19.1 10 19.2 10 19.3 40 2.1 57 2.2 20 2.3 30 2.4 73
20.1 15 20.2 11 20.3 63 21 43 22 27 23.1 12 23.2 5 23.3 46 24.1 57
24.2 55 25.1 37 25.2 30 26 22 27.1 9 27.2 51 28.1 7 28.2 6 28.3 27
29.1 4 29.2 3 29.3 15 30.1 13 30.2 11 3.1 38 3.2 97 3.3 90 3.4 62
3.5 64 3.6 89 3.7 40 3.8 65 3.9 20 4.1 98 4.10 42 4.11 18 4.12 69
4.13 20 4.14 11 4.2 60 4.3 27 4.4 72 4.5 51 4.6 28 4.7 45 4.8 10
4.9 63 5.1 72 5.2 19 5.3 48 5.4 61 5.5 91 6 30 7 27 8.1 43 8.2 18
9.1 28 9.2 18 27.1A 5.4 27.1B 30 31 5.2 32 15 33 16 34 26 35 17 36
19 37 27 38 5.3 39 28 40 31 41 9.0 42 8.1 43 32 44 45 45 34 46 46
47 38 48 11 49 47 50 7.8
Determination of Aqueous Solubility from DMSO Stock Solutions
("Kinetic Solubility Method")
[0450] The aqueous solubility of examples of this invention is
determined by comparing the amount dissolved in buffer to the
amount dissolved in an acetonitrile/water (1/1) solution. Starting
from a 10 mM DMSO stock solution, aliquots are diluted with
acetonitrile/water (1/1) and McIlvaine buffer pH 6.8, respectively.
After 24 h of shaking, the liquid phase is filtered and analyzed by
LC-UV. The amount dissolved in buffer is compared to the amount
dissolved in the acetonitrile/water (1/1) solution. Solubility is
measured from 0.001 to 0.125 mg/ml at a DMSO concentration of 2.5%.
According to this method, the aqueous solubility at pH 6.8 of
example 4.14 is determined to be 0.076 mg/mL and the aqueous
solubility at pH 6.8 of example 27.1A is determined to be 0.081
mg/mL.
Combinations
[0451] The compounds of general formula I may be used on their own
or combined with other active substances of formula I according to
the invention. The compounds of general formula I may optionally
also be combined with other pharmacologically active substances.
These include, B2-adrenoceptor-agonists (short and long-acting),
anti-cholinergics (short and long-acting), anti-inflammatory
steroids (oral and topical corticosteroids), cromoglycate,
methylxanthine, dissociated-glucocorticoidmimetics, PDE3
inhibitors, PDE4-inhibitors, PDE7-inhibitors, LTD4 antagonists,
EGFR-inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4
derivatives, 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, MC.sup.3R, 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.
[0452] 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.: [0453] Betamimetics with
corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or
LTD4-antagonists, [0454] Anticholinergics with betamimetics,
corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or
LTD4-antagonists, [0455] Corticosteroids with PDE4-inhibitors,
CRTH2-inhibitors or LTD4-antagonists [0456] PDE4-inhibitors with
CRTH2-inhibitors or LTD4-antagonists [0457] CRTH2-inhibitors with
LTD4-antagonists.
Indications
[0458] 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:
[0459] 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 is 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);
[0460] 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;
[0461] 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;
[0462] 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);
[0463] 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;
[0464] 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;
[0465] 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,
[0466] 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.
[0467] 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.
[0468] 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.
* * * * *