U.S. patent application number 15/125599 was filed with the patent office on 2017-01-12 for heteroaryl syk inhibitors.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. The applicant listed for this patent is BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Georg DAHMANN, Jennifer L. Swantek FITZGERALD, Matthias HOFFMANN, Jasna KLICIC, David James LAMB, Clive McCARTHY, Spencer NAPIER, Karen PARRISH, John SCOTT, Edward WALKER.
Application Number | 20170008896 15/125599 |
Document ID | / |
Family ID | 52706148 |
Filed Date | 2017-01-12 |
United States Patent
Application |
20170008896 |
Kind Code |
A1 |
DAHMANN; Georg ; et
al. |
January 12, 2017 |
HETEROARYL SYK INHIBITORS
Abstract
The invention relates to new substituted heteroaryls of formula
1 wherein A is selected from the group consisting of N and CH D is
selected from the group consisting of CH, N, NH, E is C, T is
selected from the group consisting of C and N, G is selected from
the group consisting of C and N, and wherein each of the broken
(dotted) double bonds in ring 1 are selected from either a single
bond or a double bond under the proviso that all single and double
bonds of ring 1 are arranged in such a way that they all form
together with ring 2 an aromatic ring system, and wherein R.sup.1,
M and R.sup.3 are defined according to claim 1, and to the above
compounds for the treatment of a disease selected from the group
consisting of asthma, COPD, allergic rhinitis, allergic dermatitis,
lupus erythematodes, lupus nephritis and rheumatoid arthritis.
##STR00001##
Inventors: |
DAHMANN; Georg; (Biberach an
der Riss, DE) ; HOFFMANN; Matthias; (Mittelbiberach,
DE) ; KLICIC; Jasna; (Geneva, CH) ; LAMB;
David James; (Mittelbiberach, DE) ; McCARTHY;
Clive; (Wantage, GB) ; NAPIER; Spencer;
(Abingdon, GB) ; PARRISH; Karen; (Abingdon,
GB) ; SCOTT; John; (Abingdon, GB) ;
FITZGERALD; Jennifer L. Swantek; (Ridgefield, CT) ;
WALKER; Edward; (Didcot, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BOEHRINGER INGELHEIM INTERNATIONAL GMBH |
Ingelheim am Rhein |
|
DE |
|
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim am Rhein
DE
|
Family ID: |
52706148 |
Appl. No.: |
15/125599 |
Filed: |
March 12, 2015 |
PCT Filed: |
March 12, 2015 |
PCT NO: |
PCT/EP2015/055242 |
371 Date: |
September 13, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61955487 |
Mar 19, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
35/00 20180101; A61K 45/06 20130101; A61P 17/02 20180101; C07D
403/12 20130101; C07D 417/14 20130101; A61K 31/4545 20130101; A61P
7/00 20180101; A61P 9/10 20180101; C07D 487/04 20130101; A61K
31/437 20130101; A61P 11/02 20180101; A61P 13/12 20180101; A61P
7/04 20180101; A61P 11/00 20180101; A61P 27/02 20180101; A61K
31/496 20130101; A61P 1/06 20180101; A61P 5/38 20180101; A61K 31/55
20130101; A61P 37/00 20180101; A61P 1/04 20180101; A61P 1/16
20180101; A61P 21/04 20180101; C07D 413/12 20130101; A61P 7/06
20180101; A61P 21/02 20180101; C07D 403/14 20130101; A61P 19/00
20180101; A61P 25/00 20180101; A61P 37/08 20180101; A61P 15/14
20180101; A61K 31/4184 20130101; C07D 498/04 20130101; A61P 1/00
20180101; A61P 43/00 20180101; C07D 513/04 20130101; A61K 31/5377
20130101; A61P 19/10 20180101; A61P 25/02 20180101; A61P 7/10
20180101; A61P 11/06 20180101; A61P 31/12 20180101; C07D 401/14
20130101; A61K 31/416 20130101; A61P 17/00 20180101; A61P 27/14
20180101; A61P 29/00 20180101; A61P 19/02 20180101; A61K 31/454
20130101; A61P 11/08 20180101; A61P 35/02 20180101; A61P 19/08
20180101; C07D 519/00 20130101; A61P 37/02 20180101; A61K 31/427
20130101; A61K 31/519 20130101; A61K 31/444 20130101; A61P 17/06
20180101; C07D 417/12 20130101; C07D 471/04 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; A61K 31/4184 20060101 A61K031/4184; A61K 31/519
20060101 A61K031/519; C07D 403/14 20060101 C07D403/14; A61K 45/06
20060101 A61K045/06 |
Claims
1. Compound of formula 1 or 1' ##STR00077## wherein A is selected
from the group consisting of N and CH D is selected from the group
consisting of CH, N, NH, E is C T is selected from the group
consisting of C and N, G is selected from the group consisting of C
and N, and wherein each of the broken (dotted) double bonds in ring
1 are selected from either a single bond or a double bond under the
proviso that all single and double bonds of ring 1 are arranged in
such a way that they all form together with ring 2 an aromatic ring
system, and wherein M is selected from the group consisting of
--CH.sub.2--, --O--, --NH-- and --N(C.sub.1-4-alkyl)-; R.sup.3 is
selected from the group consisting of methyl and ethyl; Het is
selected from the group consisting of a five- to six-membered
monocyclic heterocycle with 1, 2, 3 or 4 heteroatoms each
independently from one another selected from N, S and O, and a
nine- to eleven-membered bicyclic heterocycle with 1, 2, 3 or 4
heteroatoms each independently from one another selected from N, S
and O; Hetaryl is selected from the group consisting of a five- to
six-membered monocyclic heteroaromate with 1, 2, 3 or 4 heteroatoms
each independently from one another selected from N, S and O; and a
nine- to eleven-membered bicyclic heteroaromate with 1, 2, 3 or 4
heteroatoms each independently from one another selected from N, S
and O; and wherein R.sup.1 is selected from the group consisting of
Het and Hetaryl; which is optionally further substituted by one,
two or three substituents Z, whereby each Z is a substituent
selected from the group consisting of --OH, oxo, --CN, halogen,
--C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl,
three- to seven-membered cycloalkyl, Het, Hetaryl,
--CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
--OH, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het, Hetaryl,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, whereby
substituent X is optionally further substituted by one, two or
three substituents of a group selected from oxo, --OH, halogen and
C.sub.1-3-alkyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
2. (canceled)
3. The compound of formula 1 according to claim 1 or of formula 1'
of claim 1, wherein M is --CH.sub.2-- and wherein R.sup.3 is
methyl, and wherein R.sup.1 is selected from the group consisting
of Het and Hetaryl; which is optionally further substituted by one,
two or three substituents Z, whereby each Z is a substituent
selected from the group consisting of --OH, oxo, --CN, halogen,
--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to seven-membered
cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, alkyl, --C.sub.1-4-haloalkyl,
--O--(C.sub.1-4-alkylene)-Het, Het, Hetaryl, --NH.sub.2, whereby
substituent X is optionally further substituted by one, two or
three substituents of a group selected from oxo, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the
pharmaceutically acceptable salts of the aforementioned
compounds.
4. The compound of formula 1d according to claim 1 ##STR00078## or
of formula 1d' according to claim 1, ##STR00079## wherein A is
selected from the group consisting of N and CH, R.sup.1 is selected
from the group consisting of Het and Hetaryl; which is optionally
further substituted by one, two or three substituents Z, whereby
each Z is a substituent selected from the group consisting of --OH,
oxo, --CN, halogen, --C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--C.sub.1-6-haloalkyl, three- to seven-membered cycloalkyl, Het,
Hetaryl, --CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
5. The compound of formula 1d or of formula 1d' according to claim
4, wherein A is CH and wherein R.sup.1 is either a monocyclic five-
to six-membered heteroaromate with 1, 2 or 3 heteroatoms each
independently from one another selected from the group consisting
of N, O and S, or a 9- to 11-membered bicyclic heteroaromate with
1, 2, 3 or 4 heteroatoms each independently from one another
selected from the group consisting of N, O and S, wherein this
R.sup.1-residue is attached to the rest of the molecule either via
a C-atom or via an N-atom and is optionally further substituted by
one, two or three substituents Z, whereby each Z is a substituent
selected from the group consisting of --OH, oxo, --CN, halogen,
-methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, --O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
1'(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
6. The compound of formula 1d or of formula 1d' according to claim
4, wherein R.sup.1 is selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl,
imidazo-pyridinyl and indolyl, wherein this R.sup.1-residue is
attached to the rest of the molecule either via a C-atom or via an
N-atom and is optionally further substituted by one, two or three
substituents Z, whereby each Z is a substituent selected from the
group consisting of --OH, oxo, --CN, halogen, -methyl, -ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, --O-methyl,
--O-ethyl, O-propyl, O-butyl, --C.sub.1-3-haloalkyl, three-, four,
five- or six-membered cycloalkyl, Het, Hetaryl,
--CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
7. The compound of formula 1d or of formula 1d' according to claim
4, which is ##STR00080## and the pharmaceutically acceptable salts
of the aforementioned compounds.
8. The compound of formula 1e according to claim 1, ##STR00081## or
of formula 1e' according to claim 1, ##STR00082## wherein A is
selected from the group consisting of N and CH R.sup.1 is selected
from the group consisting of Het and Hetaryl; which is optionally
further substituted by one, two or three substituents Z, whereby
each Z is a substituent selected from the group consisting of --OH,
oxo, --CN, halogen, --C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl,
three- to seven-membered cycloalkyl, Het, Hetaryl,
--CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.)
9. The compound of formula 1e or of formula 1e' according to claim
8, wherein A is CH and wherein R.sup.1 is a monocyclic five- to
six-membered heteroaromate with 1, 2 or 3 heteroatoms each
independently from one another selected from the group consisting
of N, O and S, or a 9- to 11-membered bicyclic heteroaromate with
1, 2, 3 or 4 heteroatoms each independently from one another
selected from the group consisting of N, O and S, wherein this
R.sup.1-residue is attached to the rest of the molecule either via
a C-atom or via an N-atom and is optionally further substituted by
one, two or three substituents Z, whereby each Z is a substituent
selected from the group consisting of --OH, oxo, --CN, halogen,
-methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, --O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
10. The compound of formula 1e or of formula 1e' according to claim
8, wherein R.sup.1 is selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl,
imidazo-pyridinyl and indolyl, wherein this R.sup.1-residue is
attached to the rest of the molecule either via a C-atom or via an
N-atom and is optionally further substituted by one, two or three
substituents Z, whereby each Z is a substituent selected from the
group consisting of --OH, oxo, --CN, halogen, -methyl, -ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, --O-methyl,
--O-ethyl, O-propyl, O-butyl, --C.sub.1-3-haloalkyl, three-, four,
five- or six-membered cycloalkyl, Het, Hetaryl,
--CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
11. The compound of formula 1e or of formula 1e' according to claim
8, which is ##STR00083## and the pharmaceutically acceptable salts
of the aforementioned compound.
12. The compound of formula 1f according to claim 1, ##STR00084##
or of formula 1f'0 according to claim 1, ##STR00085## wherein
R.sup.1 is selected from the group consisting of Het and Hetaryl;
which is optionally further substituted by one, two or three
substituents Z, whereby each Z is a substituent selected from the
group consisting of --OH, oxo, --CN, halogen, --C.sub.1-6-alkyl,
--C.sub.1-6-haloalkyl, three- to seven-membered cycloalkyl, Het,
Hetaryl, --CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
13. The compound of formula 1f or of formula 1f' according to claim
12, wherein R.sup.1 is either a monocyclic five- to six-membered
heteroaromate with 1, 2 or 3 heteroatoms each independently from
one another selected from the group consisting of N, O and S, or a
9- to 11-membered bicyclic heteroaromate with 1, 2, 3 or 4
heteroatoms each independently from one another selected from the
group consisting of N, O and S, wherein this R.sup.1-residue is
attached to the rest of the molecule either via a C-atom or via an
N-atom and is optionally further substituted by one, two or three
substituents Z, whereby each Z is a substituent selected from the
group consisting of --OH, oxo, --CN, halogen, -methyl, -ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
--O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
14. The compound of formula 1f or of formula 1f' according to claim
12, wherein R.sup.1 is selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl,
imidazo-pyridinyl and indolyl, wherein this R.sup.1-residue is
attached to the rest of the molecule either via a C-atom or via an
N-atom and is optionally further substituted by one, two or three
substituents Z, whereby each Z is a substituent selected from the
group consisting of --OH, oxo, --CN, halogen, -methyl, -ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, --O-methyl,
--O-ethyl, O-propyl, O-butyl, --C.sub.1-3-haloalkyl, three-, four,
five- or six-membered cycloalkyl, Het, Hetaryl,
--CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het, which is
optionally further substituted by one, two or three substituents X,
whereby each X is selected from the group consisting of halogen,
oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2, whereby substituent X is optionally further substituted
by one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
15. The compound of formula 1 according to formula 1f or of 1f' of
claim 12 which is ##STR00086## and the pharmaceutically acceptable
salts thereof.
16. An intermediate compound selected from the group consisting of
formula 6 ##STR00087## of formula 7 ##STR00088## of formula 8
##STR00089## and of formula 11 ##STR00090## wherein E, D, G, T and
R.sup.1 are defined as in claim 1 and wherein Hal is Cl or Br and
wherein PG is a protecting group selected from the group consisting
of benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl.
17. An intermediate compound selected from the group consisting of
formula 10.3 ##STR00091##
18. A method for the treatment of a disease which can be treated by
inhibition of the SYK enzyme comprising administering a
therapeutically effective amount of a compound of claim 1 to a
patient in need thereof.
19. The method of claim 18 for the treatment of a disease selected
from the group consisting of allergic rhinitis, asthma, COPD, adult
respiratory distress syndrome, bronchitis, B-cell lymphoma,
dermatitis and contact dermatitis, allergic dermatitis, allergic
rhinoconjunctivitis, rheumatoid arthritis, anti-phospholipid
syndrome, Berger's disease, Evans's syndrome, ulcerative colitis,
allergic antibody-based glomerulonephritis, granulocytopenia,
Goodpasture's syndrome, hepatitis, Henoch-Schonlein purpura,
hypersensitivity vasculitis, immunohaemolytic anaemia, autoimmune
haemolytic anemia, idiopathic thrombocytopenic purpura, Kawasaki
syndrome, allergic conjunctivitis, lupus erythematodes, lupus
nephritis, capsule cell lymphoma, neutropenia, non-familial lateral
sclerosis, artheriosclerosis, Crohn's disease, multiple sclerosis,
myasthenia gravis, osteoporosis, osteolytic diseases, osteopenia,
psoriasis, Sjogren's syndrome, sclerodermy, T-cell lymphoma,
urticaria/angiooedema, Wegener's granulomatosis and coeliac
disease.
20. The method according to claim 19 wherein the disease is
selected from the group consisting of asthma, COPD, allergic
rhinitis, adult respiratory distress syndrome, bronchitis, allergic
dermatitis, contact dermatitis, idiopathic thrombocytopenic
purpura, rheumatoid arthritis, lupus erythematodes, lupus nephritis
and allergic rhinoconjunctivitis.
21. The method according to claim 20 wherein the disease is
selected from the group consisting of asthma, COPD, allergic
rhinitis, allergic dermatitis, lupus erythematodes, lupus nephritis
and rheumatoid arthritis.
22. Pharmaceutical formulations, characterised in that they contain
one or more compounds according to claim 1 and a pharmaceutically
acceptable excipient.
23. Pharmaceutical formulations, characterised in that they contain
one or more compounds according to claim 1 in combination with an
active substance selected from the group consisting of
anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors,
EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors,
iNOS-inhibitors, CRTH2-antagonists, HMG-CoA reductase inhibitors
and NSAIDs.
Description
[0001] The invention relates to new substituted heteroaryls of
formula 1
##STR00002##
or of formula 1'
##STR00003##
wherein
[0002] A is selected from the group consisting of N and CH
[0003] D is selected from the group consisting of CH, N, NH,
[0004] E is C,
[0005] T is selected from the group consisting of C and N,
[0006] G is selected from the group consisting of C and N,
[0007] and wherein each of the broken (dotted) double bonds in ring
1 are selected from either a single bond or a double bond under the
proviso that all single and double bonds of ring 1 are arranged in
such a way that they all form together with ring 2 an aromatic ring
system,
[0008] and wherein
[0009] M, R.sup.3 and R.sup.1 are defined as in claim 1. Further
the invention relates to the above compounds of formula 1 or of
formula 1' for the treatment of a disease selected from the group
consisting of asthma, COPD, allergic rhinitis, allergic dermatitis,
lupus erythematodes, lupus nephritis and rheumatoid arthritis.
1. BACKGROUND TO THE INVENTION
[0010] 1.1 SYK-Inhibitors
[0011] The present invention describes new compounds that inhibit
the protein kinase Syk (spleen tyrosine kinase), the preparation
and formulation thereof and their use for preparing a
medicament.
[0012] Syk is an intracellular tyrosine kinase that has an
important mediator function in the signal transduction of different
receptors in B-cells, mast cells, monocytes, macrophages,
neutrophils, T-cells, dendritic cells and epithelial cells. The
receptors in which Syk performs an important function in signal
transduction include for example the receptors for IgE
(Fc.epsilon.RI) and IgG (Fc.gamma.R1) on mast cells and B cells,
the B-cell receptor (BCR) and the T-cell receptor (TCR) on B- and
T-cells, the ICAM1 receptor (ICAM1R) on epithelial cells of the
respiratory tract, the DAP12-receptor on natural killer cells,
dendritic cells and osteoclasts, the dectin 1-receptor on a
subpopulation of T-helper cells (Th-17 cells), as well as the
integrin receptors for .sym.1-, .beta.2- and .beta.3-integrins on
neutrophils, monocytes and macrophages (Wong et al.; Expert Opin.
Investig. Drugs (2004) 13(7), 743-762; Ulanova et al.; Expert
Opion. Ther. Target (2005) 9(5); 901-921; Wang et al.; J. Immunol.
(2006) 177, 6859-6870; Leib and Gut-Landmann et al.; Nature
Immunology (2007) 8, 630-638; Slack et al., European J. Immunol.
(2007) 37, 1600-1612). The molecular processes are described best
for the signal transduction of the Fc.epsilon.RI. In mast cells the
binding of IgE to Fc.epsilon.RI causes the cross-linking of
IgE-receptors and the recruiting and activation of Lyn (a tyrosine
kinase from the Src family). Active Lyn phoshorylates so-called
ITAM motifs, which are present in many of the receptors listed
above, and thereby generates binding sites for the SH2-domain of
Syk. As a result of the binding to the ITAM motif Syk is activated
and then phosphorylates various substrates which are needed for the
release of allergic and inflammatory mediators such as e.g.
histamine and .beta.-hexosamidase (.beta.HA), as well as for the
synthesis of lipid mediators, such as e.g. prostaglandins and
leukotrienes.
[0013] In view of its central function in different signal
transduction pathways Syk has been discussed as a therapeutic
target for different diseases such as e.g. allergic rhinitis,
asthma, autoimmune diseases, rheumatoid arthritis, osteopenia,
osteoporosis, COPD and various leukaemias and lymphomas (Wong et
al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; Ulanova et
al.; Expert Opion. Ther. Target (2005) 9(5); 901-921; Sigh and
Masuda. Annual Reports in Medicinal Chemistry (2007) Vol 42;
379-391; Bajpai et al.; Expert Opin. Investig. Drugs (2008) Vol 15
(5); 641-659; Masuda and Schmitz; PPT (2008) Vol 21; 461-467;
Riccaboni et al., Drug Discovery Today (2010) Vol 00 (0); 517-530;
Efremov and Luarenti, Expert Opin Investig Drugs. (2011)
20(5):623-36).
[0014] Allergic rhinitis and asthma are diseases associated with
allergic reactions and inflammatory processes and involving
different cell types such as e.g. Mast cells, eosinophils, T-cells
and dendritic cells. After exposure to allergens has occurred, the
high affinity immunoglobulin receptors for IgE (Fc.epsilon.RI) and
IgG (Fc.gamma.R1) are activated and induce the release of
pro-inflammatory mediators and bronchoconstrictors. An inhibitor of
the Syk kinase activity should thus be able to inhibit these
steps.
[0015] Rheumatoid arthritis (RA) is an autoimmune disease in which
the bones and ligaments structures surrounding the joints are
progressively destroyed. In the pathophysiology of RA, B-cells play
a significant role, as has been demonstrated for example by the
therapeutic use of rituximab, a B cell-depleting antibody. In
addition to the function of Syk in the signal transduction of the
BCR (which after being stimulated also induces the release of
pro-inflammatory mediators), Syk also plays an important part in
the maturation and proliferation of B cells (Cheng et al. Nature
(1995) 378, 303-306, Cornall et al., PNAS (2000) 97(4), 1713-1718).
An inhibitor of the Syk kinase activity may thus offer a
therapeutic option for the treatment of autoimmune diseases such as
RA and diseases with an increased proliferation of B cells, such as
e.g. B-cell lymphomas.
[0016] Chronic obstructive pulmonary disease (COPD) is
characterised by a successive deterioration in lung function and
chronic inflammation of the airways, which is initiated and
produced by noxious substances of all kinds and contributes to the
maintenance of the course of the disease. At a cellular level, in
COPD there is in particular a multiplication of T-lymphocytes,
neutrophils, granulocytes and macrophages. In particular, there is
an increase in the number of CD8-positive lymphocytes, that is
directly connected with the impairment of lung function. Another
characteristic of COPD are acute deteriorations in lung function
(exacerbations), characterised by viral (e.g. Rhinovirus), or
bacterial (e.g. Streptococcus pneumoniae, Haemophilus influenzae
and Moraxella catarrhalis) infections.
[0017] In view of the pro-inflammatory function of Syk in
macrophages, T-cells and neutrophils as described above (see: Wong
et al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; and
references cited therein) an inhibitor of the Syk kinase activity
could be a new therapeutic approach to the treatment of the
inflammatory processes that underlie COPD. It has also been shown
that Syk in epithelial cells of the respiratory tract is involved
in the ICAM1R-mediated uptake and subsequent replication of the
Rhinovirus and that a si-RNA against Syk blocks these steps (Wang
et al.; J. Immunol. (2006) 177, 6859-6870; Lau et al.; J. Immunol.
(2008) 180, 870-880). Thus, an inhibitor of the Syk kinase activity
could also be used therapeutically in exacerbations caused by
Rhinoviruses.
[0018] Various studies suggest that Syk is involved in the
malignant transformation of lymphocytes (summarised in Sigh and
Masuda, Annual Reports in Medicinal Chemistry (2007) Vol 42;
379-391). A TEL-Syk fusion protein with a constitutive Syk activity
transformed B cells of a patient with myelodysplastic syndrome, a
constitutively active ITK-Syk fusion protein was isolated from
patients with peripheral T-cell lymphomas (PTCL). Moreover,
constitutively active Syk was found in B-cell lymphoma cells of
patients, especially in B-lineage acute lymphoblastic leukemia
(B-ALL), follicular lymphoma (FL), diffuse large B-cell lymphoma
(DLBCL), mantle cell lymphomas and B cell Non-Hodgkin Lymphomas
(NHLs) as well as in acute myeloid leukemia (AML). On the basis of
these data it seems that Syk is a proto-oncogene in haematopoietic
cells and represents a potential target for the treatment of
certain leukaemias and lymphomas.
[0019] Idiophathic thrombocytopenic purpura (ITP) is an autoimmune
disease in which IgG autoantibodies against antigens present on
platelets bind to and destroy platelets. Patients with ITP have an
accelerated clearence of circulating IgG-coated platelets via
macrophages in the spleen and the liver. In view of the
pro-inflammatory Fc.gamma.R-mediated function of Syk in macrophages
an inhibitor of Syk is considered to have a therapeutic benefit in
Fc.gamma.R-mediated cytopenias like ITP. Indeed the Syk inhibitor
R788 (R406) improved platelet counts in a single center, oben label
study in patients with ITP (Podolanczuk et al; Blood (2009) 113,
3154-3169).
[0020] Bullous pemphigoid (Ujiie et al. Journal of Dermatology
2010; 37: 194-204) is a chronic, autoimmune, subepidermal,
blistering skin disease that rarely involves mucous membranes.
Bullous pemphigoid is characterized by the presence of
immunoglobulin G (IgG) autoantibodies specific for the
hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180
(BPAg2). Pemphigus vulgaris (Venugopal et al. Dermatol. Clin. 2011;
29:373-80) is a chronic blistering skin disease with skin lesions
that are rarely pruritic, but which are often painful. Pemphigus
vulgaris is an autoimmune disease caused by IgG autoantibodies
directed against both desmoglein 1 and desmoglein 3 resulting in
the loss of cohesion between keratinocytes in the epidermis. It is
characterized by extensive flaccid blisters and mucocutaneous
erosions. In both diseases IgG autoantibodies bind to Fc receptor
gamma (FcR.gamma.) and activate FcR.gamma. and downstream signaling
via Syk kinase. Thus, an inhibitor of the Syk kinase activity which
blocks downstream signalling of the FcRg could be used
therapeutically to treat patients with bullous pemphigoid and
pemphigus vulgaris.
[0021] Systemic lupus erythematosus (SLE) is a chronic autoimmune
disease which can affect basically any organ of the body. It is
characterised by a multisystem inflammation of the microvascular
and the presence of autoantibodies. Fc.gamma.R-deficient mice are
protected from several aspects of SLE in disease-related
preclinical models, suggesting that an inhibitor of Syk can have a
therapeutic benefit in SLE in view of the pro-inflammatory
Fc.gamma.R-mediated function of Syk in various cells.
[0022] 1.2 Prior Art
[0023] 1,6-Naphthyridines are known as SYK-inhibitors. For example
U.S. Pat. No. 3,928,367, U.S. Pat. No. 4,017,500, U.S. Pat. No.
4,115,395 and U.S. Pat. No. 4,260,759 describe
5-amino-1,6-naphthyridines with an antifungal and antibacterial
activity. Further, WO 9918077 describes
5-piperazinyl-1,6-naphthyridines as serotonin antagonists.
Additionally, U.S. Pat. No. 7,321,041 describes substituted
1,6-naphthyridines as SYK-inhibitors, however these
1,6-naphthyridines have a completely different substitution pattern
from the compounds according to the invention. Also WO 2011092128
discloses 1,6-naphthyridines which are substituted in 5- and in
7-position.
[0024] In WO 2012/167733, WO 2012/167423 and in WO 2012/123312
other naphthryidine derivatives such as pyrido[3,4-b]pyrazines
which were also substituted in 5- and in 7-position have been
disclosed as SYK-inhibitors.
[0025] Additionally, WO 01/83485 discloses substituted
imidazopyrimidines and triazolopyrimidines as SYK-inhibitors,
whereas WO 2008/113469 discloses substituted imidazo- and
triazolopyrimidines as GSK 3.beta.-inhibitors.
[0026] Also quinolones are known as SYK-inhibitors. For instance,
WO 2006038041 and WO 2013014060 both disclose quinoline-compounds
which are substituted in the 5- and 7-position, however the
substitution pattern--in particular in the 7-position--is
completely different from the one of the compounds of formula 1 of
the instant invention.
[0027] Surprisingly it has now been found that the compounds of
formulas 1 and 1' and in particular the compounds of formulas 1d,
1d', 1e, 1e', 1f or 1f' are particularly suitable for the treatment
of respiratory complaints, allergic diseases, osteoporosis,
gastrointestinal diseases, autoimmune diseases, inflammatory
diseases and diseases of the peripheral or central nervous system,
particularly for the treatment of asthma, allergic rhinitis,
rheumatoid arthritis, allergic dermatitis, lupus erythematosus
(SLE) and COPD, in particular because all these compounds of the
present invention show the following desired capacities: [0028]
high SYK inhibition (reflected by "low" IC.sub.50-values with
respect to SYK-inhibition) [0029] very low inhibition of the kinase
Aurora B (reflected by "high" IC.sub.50-values with respect to
inhibition of AURB) [0030] low inhibition of the kinase FLT-3
(reflected by "high" IC.sub.50-values with respect to inhibition of
FLT-3) [0031] low inhibition of the kinase GSK3.beta. (reflected by
"high" IC.sub.50-values with respect to inhibition of
GSK3.beta.)
[0032] This was completely surprising for a person skilled in the
art, since the compounds of formula 1 and 1' of the instant
invention have several significant structural differences compared
to the previously known prior art compounds. For instance the
compounds of formula 1 and 1' of the instant invention differ from
the previously known 1,6-naphthyridines, quinolones,
pyrido[3,4-b]pyrazines, imidazopyrimidines and triazolopyrimidines
therein that they combine the following features: [0033] they all
possess diverse core modifications in the central bicyclic
heteroaromatic ring system [0034] that they all have a
methyl-group-substitution attached to position E in formula 1
and/or 1' and [0035] that they all possess a residue of formula
T
##STR00004##
[0035] preferably a residue of formula T'
##STR00005##
2. DESCRIPTION OF THE INVENTION
[0036] The present invention concerns compounds of formula 1
##STR00006##
wherein
[0037] A is selected from the group consisting of N and CH
[0038] D is selected from the group consisting of CH, N, NH,
[0039] E is C,
[0040] T is selected from the group consisting of C and N,
[0041] G is selected from the group consisting of C and N,
and wherein each of the broken (dotted) double bonds in ring 1 are
selected from either a single bond or a double bond under the
proviso that all single and double bonds of ring 1 are arranged in
such a way that they all form together with ring 2 an aromatic ring
system, and wherein
[0042] M is selected from the group consisting of --CH.sub.2--,
--O--, --NH-- and --N(C.sub.1-4-alkyl)-;
[0043] R.sup.3 is selected from the group consisting of methyl and
ethyl;
[0044] Het is selected from the group consisting of
[0045] a five- to six-membered monocyclic heterocycle with 1, 2, 3
or 4 heteroatoms each independently from one another selected from
N, S and O,
[0046] and a nine- to eleven-membered bicyclic heterocycle with 1,
2, 3 or 4 heteroatoms each independently from one another selected
from N, S and O;
[0047] Hetaryl is selected from the group consisting of
[0048] a five- to six-membered monocyclic heteroaromate with 1, 2,
3 or 4 heteroatoms each independently from one another selected
from N, S and O;
[0049] and a nine- to eleven-membered bicyclic heteroaromate with
1, 2, 3 or 4 heteroatoms each independently from one another
selected from N, S and O;
[0050] and wherein
[0051] R.sup.1 is selected from the group consisting of
[0052] Het and Hetaryl;
[0053] which is optionally further substituted by one, two or three
substituents Z,
[0054] whereby each Z is a substituent selected from the group
consisting of
[0055] --OH, oxo, --CN, halogen, --C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0056] which is optionally further substituted by one, two or three
substituents X,
[0057] whereby each X is selected from the group consisting of
halogen, --OH, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het, Hetaryl,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2,
[0058] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo, --OH,
halogen and C.sub.1-3-alkyl,
[0059] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0060] A preferred embodiment of the instant invention relates to
the aforementioned compounds of formula 1'
##STR00007##
wherein residues A, D, E, T, G, Het, Hetaryl, R.sup.1 and R.sup.3
are defined as mentioned above, and the pharmaceutically acceptable
salts of the aforementioned compounds.
[0061] In a further preferred embodiment the instant invention
concerns the aforementioned compounds of formula 1 or of formula
1',
[0062] wherein
[0063] M is --CH.sub.2--
[0064] and wherein
[0065] R.sup.3 is methyl,
[0066] and wherein
[0067] R.sup.1 is selected from the group consisting of
[0068] Het and Hetaryl;
[0069] which is optionally further substituted by one, two or three
substituents Z,
[0070] whereby each Z is a substituent selected from the group
consisting of
[0071] --OH, oxo, --CN, halogen, --C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0072] which is optionally further substituted by one, two or three
substituents X,
[0073] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het, Hetaryl,
--NH.sub.2,
[0074] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0075] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0076] In a further preferred embodiment the invention concerns
compounds of formula 1d
##STR00008##
[0077] or of formula 1d',
##STR00009##
[0078] wherein
[0079] A is selected from the group consisting of N and CH,
[0080] R.sup.1 is selected from the group consisting of
[0081] Het and Hetaryl;
[0082] which is optionally further substituted by one, two or three
substituents Z,
[0083] whereby each Z is a substituent selected from the group
consisting of --OH, oxo, --CN, halogen, --C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O---(C.sub.1-3-alkyl), --O-Het,
[0084] which is optionally further substituted by one, two or three
substituents X,
[0085] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)Het, Het,
--NH.sub.2,
[0086] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0087] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0088] In another preferred embodiment the instant invention
relates to the above compounds of the aforementioned formula 1 d or
formula 1d', wherein
[0089] A is CH
[0090] and wherein
[0091] R.sup.1 is either [0092] a monocyclic five- to six-membered
heteroaromate with 1, 2 or 3 heteroatoms each independently from
one another selected from the group consisting of N, O and S,
[0093] or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3
or 4 heteroatoms each independently from one another selected from
the group consisting of N, O and S,
[0094] wherein this R.sup.1--residue is attached to the rest of the
molecule either via a C-atom or via an N-atom and is optionally
further substituted by one, two or three substituents Z,
[0095] whereby each Z is a substituent selected from the group
consisting of
[0096] --OH, oxo, --CN, halogen, -methyl, -ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, --O--C.sub.1-6-alkyl,
--C.sub.1-6-haloalkyl, three- to seven-membered cycloalkyl, Het,
Hetaryl, --CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0097] which is optionally further substituted by one, two or three
substituents X,
[0098] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2,
[0099] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0100] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0101] In another preferred embodiment the instant invention
relates to the above compounds of the aformentioned formula 1d or
formula 1d', wherein
[0102] R.sup.1 is selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl,
imidazo-pyridinyl and indolyl,
[0103] wherein this R.sup.1--residue is attached to the rest of the
molecule either via a C-atom or via an N-atom and is optionally
further substituted by one, two or three substituents Z,
[0104] whereby each Z is a substituent selected from the group
consisting of
[0105] --OH, oxo, --CN, halogen, -methyl, -ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, --O-methyl, --O-ethyl,
O-propyl, O-butyl, --C.sub.1-3-haloalkyl, three-, four, five- or
six-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--N HCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0106] which is optionally further substituted by one, two or three
substituents X,
[0107] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O-(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2,
[0108] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0109] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0110] In a particularly preferred embodiment the instant invention
relates to the the above compound of the aforementioned formula 1d
or formula 1d', which is
##STR00010##
and the pharmaceutically acceptable salts of the aforementioned
compound.
[0111] In another preferred embodiment the instant invention
relates to compounds of formula 1e,
##STR00011##
or of formula 1e',
##STR00012##
wherein
[0112] A is selected from the group consisting of N and CH
[0113] R.sup.1 is selected from the group consisting of
[0114] Het and Hetaryl;
[0115] which is optionally further substituted by one, two or three
substituents Z,
[0116] whereby each Z is a substituent selected from the group
consisting of --OH, oxo, --CN, halogen, --C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--N HCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0117] which is optionally further substituted by one, two or three
substituents X,
[0118] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)Het, Het,
--NH.sub.2,
[0119] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl, and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0120] In a further preferred embodiment the instant invention
relates to the above compounds of the aforementioned formula 1e or
formula 1e', wherein
[0121] A is CH
[0122] and wherein
[0123] R.sup.1 is [0124] a monocyclic five- to six-membered
heteroaromate with 1, 2 or 3 heteroatoms each independently from
one another selected from the group consisting of N, O and S,
[0125] or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3
or 4 heteroatoms each independently from one another selected from
the group consisting of N, O and S,
[0126] wherein this R.sup.1--residue is attached to the rest of the
molecule either via a C-atom or via an N-atom and is optionally
further substituted by one, two or three substituents Z,
[0127] whereby each Z is a substituent selected from the group
consisting of
[0128] --OH, oxo, --CN, halogen, -methyl, -ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, --O--C.sub.1-6-alkyl,
--C.sub.1-6-haloalkyl, three- to seven-membered cycloalkyl, Het,
Hetaryl, --CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0129] which is optionally further substituted by one, two or three
substituents X,
[0130] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2,
[0131] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0132] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0133] In another preferred embodiment the instant invention
concerns the above compounds of the aforementioned formula 1e or
formula 1e', wherein
[0134] R.sup.1 is selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl,
imidazo-pyridinyl and indolyl,
[0135] wherein this R.sup.1--residue is attached to the rest of the
molecule either via a C-atom or via an N-atom and is optionally
further substituted by one, two or three substituents Z,
[0136] whereby each Z is a substituent selected from the group
consisting of
[0137] --OH, oxo, --CN, halogen, -methyl, -ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, --O-methyl, --O-ethyl,
O-propyl, O-butyl, --C.sub.1-3-haloalkyl,three-, four, five- or
six-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0138] which is optionally further substituted by one, two or three
substituents X,
[0139] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2,
[0140] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0141] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0142] In a particularly preferred embodiment the instant invention
relates to the above compound of formula 1e or of formula 1e',
which is
##STR00013##
and the pharmaceutically acceptable salts of the aforementioned
compound.
[0143] In a further preferred embodiment the instant invention
refers to compounds of formula 1f or of 1f'
##STR00014##
or of formula 1f' according to claim 2,
##STR00015##
wherein
[0144] R.sup.1 is selected from the group consisting of
[0145] Het and Hetaryl;
[0146] which is optionally further substituted by one, two or three
substituents Z,
[0147] whereby each Z is a substituent selected from the group
consisting of
[0148] --OH, oxo, --CN, halogen, --C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --C.sub.1-6-haloalkyl, three- to
seven-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0149] which is optionally further substituted by one, two or three
substituents X,
[0150] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)Het, Het,
--NH.sub.2,
[0151] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0152] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0153] In a further preferred embodiment the instant invention
relates to the above compounds of the aforementioned formula 1f or
formula 1f', wherein
[0154] R.sup.1 is either [0155] a monocyclic five- to six-membered
heteroaromate with 1, 2 or 3 heteroatoms each independently from
one another selected from the group consisting of N, O and S,
[0156] or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3
or 4 heteroatoms each independently from one another selected from
the group consisting of N, O and S,
[0157] wherein this R.sup.1--residue is attached to the rest of the
molecule either via a C-atom or via an N-atom and is optionally
further substituted by one, two or three substituents Z,
[0158] whereby each Z is a substituent selected from the group
consisting of
[0159] --OH, oxo, --CN, halogen, -methyl, -ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, --O--C.sub.1-6-alkyl,
--C.sub.1-6-haloalkyl, three- to seven-membered cycloalkyl, Het,
Hetaryl, --CO--N(CH.sub.3).sub.2, --CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0160] which is optionally further substituted by one, two or three
substituents X,
[0161] whereby each X is selected from the group consisting of
halogen, oxo, --C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl,
--C.sub.1-4-haloalkyl, --O--(C.sub.1-4-alkylene)-Het, Het,
--NH.sub.2,
[0162] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0163] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0164] In a further preferred embodiment the instant invention
relates to the above compounds of the aforementioned formula 1f or
formula 1f', wherein
[0165] R.sup.1 is selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl,
imidazo-pyridinyl and indolyl,
[0166] wherein this R.sup.1--residue is attached to the rest of the
molecule either via a C-atom or via an N-atom and is optionally
further substituted by one, two or three substituents Z,
[0167] whereby each Z is a substituent selected from the group
consisting of
[0168] --OH, oxo, --CN, halogen, -methyl, -ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, --O-methyl, --O-ethyl,
O-propyl, O-butyl, --C.sub.1-3-haloalkyl,three-, four, five- or
six-membered cycloalkyl, Het, Hetaryl, --CO--N(CH.sub.3).sub.2,
--CO--NHCH.sub.3, --CO--NH.sub.2,
--(C.sub.1-3-alkylene)-O--(C.sub.1-3-alkyl), --O-Het,
[0169] which is optionally further substituted by one, two or three
substituents X, whereby each X is selected from the group
consisting of halogen, oxo, --C.sub.1-4-alkyl,
--O--C.sub.1-4-alkyl, --C.sub.1-4-haloalkyl,
--O--(C.sub.1-4-alkylene)-Het, Het, --NH.sub.2,
[0170] whereby substituent X is optionally further substituted by
one, two or three substituents of a group selected from oxo,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
tert-butyl,
[0171] and the pharmaceutically acceptable salts of the
aforementioned compounds.
[0172] In another particularly preferred embodiment the instant
invention relates to the above compound of formula 1f or 1f', which
is
##STR00016##
and the pharmaceutically acceptable salts thereof.
[0173] In a further aspect the instant invention refers to an
intermediate compound selected from the group consisting of formula
6
##STR00017##
of formula 7
##STR00018##
of formula 8
##STR00019##
and of formula 11
##STR00020## [0174] wherein E, D, G, T and R.sup.1 are defined as
in claim 1 and wherein Hal is Cl or Br and wherein PG is a
protecting group selected from the group consisting of benzyl,
1-phenylethyl, 1-(4-methoxyphenyl)ethyl.
[0175] In a further aspect the instant invention refers to an
intermediate compound of formula 10.3
##STR00021##
[0176] In a further aspect the instant invention refers to one of
the aforementioned compounds of formula 1 or 1' (or of any of the
sub-formulas 1d, 1d', 1e, 1e', 1f or 1f') for the treatment of a
disease which can be treated by inhibition of the SYK enzyme.
[0177] In another preferred aspect the instant invention relates to
one of the aforementioned compounds of formula 1 or 1' (or of any
of the sub-formulas 1d, 1d', 1e, 1e', 1f or 1f') for the treatment
of a disease selected from the group consisting of allergic
rhinitis, asthma, COPD, adult respiratory distress syndrome,
bronchitis, B-cell lymphoma, dermatitis and contact dermatitis,
allergic dermatitis, allergic rhinoconjunctivitis, rheumatoid
arthritis, anti-phospholipid syndrome, Berger's disease, Evans's
syndrome, ulcerative colitis,allergic antibody-based
glomerulonephritis, granulocytopenia, Goodpasture's syndrome,
hepatitis, Henoch-Schonlein purpura, hypersensitivity vasculitis,
immunohaemolytic anaemia, autoimmune haemolytic anemia, idiopathic
thrombocytopenic purpura, Kawasaki syndrome, allergic
conjunctivitis, lupus erythematodes, lupus nephritis, capsule cell
lymphoma, neutropenia, non-familial lateral sclerosis,
artheriosclerosis, Crohn's disease, multiple sclerosis, myasthenia
gravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis,
Sjogren's syndrome, sclerodermy, T-cell lymphoma,
urticaria/angiooedema, Wegener's granulomatosis and coeliac
disease.
[0178] In another preferred aspect the instant invention concerns
the aforementioned compounds of formula 1 or 1' (or of any of the
sub-formulas 1d, 1d', 1e, 1e', 1f or 1f') for the treatment of a
disease selected from the group consisting of asthma, COPD,
allergic rhinitis, adult respiratory distress syndrome, bronchitis,
allergic dermatitis, contact dermatitis, idiopathic
thrombocytopenic purpura, rheumatoid arthritis, lupus
erythematodes, lupus nephritis and allergic
rhinoconjunctivitis.
[0179] In another particularly preferred aspect the instant
invention concerns the aforementioned compounds of formula 1 or 1'
(or of any of the sub-formulas 1d, 1d', 1e, 1e', 1f or 1f') for the
treatment of a disease selected from the group consisting of
asthma, COPD, allergic rhinitis, allergic dermatitis, lupus
erythematodes, lupus nephritis and rheumatoid arthritis.
[0180] In another preferred aspect the instant invention concerns
pharmaceutical formulations which contain one or more of the
aforementioned compounds of formula 1 or 1' (or of any of the
sub-formulas 1d, 1d', 1e, 1e', 1f or 1f') and a pharmaceutically
acceptable excipient.
[0181] In another preferred aspect the instant invention concerns
pharmaceutical formulations which contain one or more compounds of
the aforementioned compounds of formula 1 or 1' (or of any of the
sub-formulas 1d, 1d', 1e, 1e', 1f or 1f') in combination with an
active substance selected from the group consisting of
anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors,
EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors,
iNOS-inhibitors, CRTH2-antagonists, HMG-CoA reductase inhibitors
and NSAIDs.
3. TERMS AND DEFINITIONS USED
[0182] Unless stated otherwise, all the substituents are
independent of one another. If for example a number of
C.sub.1-6-alkyl groups are possible substituents at a group, in the
case of three substituents, for example, C.sub.1-6-alkyl could
represent, independently of one another, a methyl, an n-propyl and
a tert-butyl.
[0183] Within the scope of this application, in the definition of
possible substituents, these may also be presented in the form of a
structural formula. An asterisk (*) in the structural formula of
the substituent is to be understood as being the linking point to
the rest of the molecule. Mor3eover, the atom of the substituent
following the linking point is understood as being the atom in
position number 1. Thus for example the groups N-piperidinyl (I),
4-piperidinyl (II), 2-tolyl (III), 3-tolyl (IV) and 4-tolyl (V) are
represented as follows:
##STR00022##
[0184] If there is no asterisk (*) in the structural formula of the
substituent, each hydrogen atom may be removed at the substituent
and the valency thus freed may serve as a binding site to the rest
of a molecule. Thus, for example, VI
##STR00023##
may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.
[0185] Alternatively to the * within the scope of this application
X.sub.1 is also understood as being the linking point of the group
R.sup.1 to the structure of formula 1 and X.sub.2 as being the
linking point of the group R.sup.2 to the structure of formula
1.
[0186] By the term "C.sub.1-6-alkyl" (including those which are
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 6 carbon atoms and by the term "C.sub.1-3-alkyl"
are meant branched and unbranched alkyl groups with 1 to 3 carbon
atoms. "C.sub.1-4-alkyl" accordingly denotes branched and
unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with
1 to 4 carbon atoms are preferred. Examples of these include:
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The
abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc., may also
optionally be used for the above-mentioned groups. Unless stated
otherwise, the definitions propyl, butyl, pentyl and hexyl include
all the possible isomeric forms of the groups in question. Thus,
for example, propyl includes n-propyl and iso-propyl, butyl
includes iso-butyl, sec-butyl and tert-butyl etc.
[0187] By the term "C.sub.1-6-alkylene" (including those which are
part of other groups) are meant branched and unbranched alkylene
groups with 1 to 6 carbon atoms and by the term
"C.sub.1-4-alkylene" are meant branched and unbranched alkylene
groups with 1 to 4 carbon atoms. Alkylene groups with 1 to 4 carbon
atoms are preferred. Examples of these include: methylene,
ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,
1,1-dimethylpropylene, 2,2-dimethylpropylene,
1,2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless
stated otherwise, the definitions propylene, butylene, pentylene
and hexylene include all the possible isomeric forms of the groups
in question with the same number of carbons. Thus, for example,
propyl includes also 1-methylethylene and butylene includes
1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.
[0188] If the carbon chain is substituted by a group which together
with one or two carbon atoms of the alkylene chain forms a
carbocyclic ring with 3, 5 or 6 carbon atoms, this includes, inter
alia, the following examples of the rings:
##STR00024##
[0189] By the term "C.sub.2-6-alkenyl" (including those which are
part of other groups) are meant branched and unbranched alkenyl
groups with 2 to 6 carbon atoms and by the term "C.sub.2-4-alkenyl"
are meant branched and unbranched alkenyl groups with 2 to 4 carbon
atoms, provided that they have at least one double bond. Alkenyl
groups with 2 to 4 carbon atoms are preferred. Examples include:
ethenyl or vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless
stated otherwise, the definitions propenyl, butenyl, pentenyl and
hexenyl include all the possible isomeric forms of the groups in
question. Thus, for example, propenyl includes 1-propenyl and
2-propenyl, butenyl includes 1-, 2- and 3-butenyl,
1-methyl-1-propenyl, 1-methyl-2-propenyl etc.
[0190] By the term "C.sub.m-alkenylene" (including those which are
part of other groups) are meant branched and unbranched alkenylene
groups with 2 to 6 carbon atoms and by the term
"C.sub.2-4-alkenylene" are meant branched and unbranched alkylene
groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4
carbon atoms are preferred. Examples of these include: ethenylene,
propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,
1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,
1,1-dimethylpropenylene, 2,2-dimethylpropenylene,
1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene.
Unless stated otherwise, the definitions propenylene, butenylene,
pentenylene and hexenylene include all the possible isomeric forms
of the groups in question with the same number of carbons. Thus,
for example, propenyl also includes 1-methylethenylene and
butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene,
1,2-dimethylethenylene.
[0191] By the term "aryl" (including those which are part of other
groups) are meant aromatic ring systems with 6 or 10 carbon atoms.
Examples include: phenyl or naphthyl, the preferred aryl group
being phenyl. Unless otherwise stated, the aromatic groups may be
substituted by one or more groups selected from among methyl,
ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine
and iodine.
[0192] By the term "aryl-C.sub.1-6-alkylene" (including those which
are part of other groups) are meant branched and unbranched
alkylene groups with 1 to 6 carbon atoms, which are substituted by
an aromatic ring system with 6 or 10 carbon atoms. Examples
include: benzyl, 1- or 2-phenylethyl or 1- or 2-naphthylethyl.
Unless otherwise stated, the aromatic groups may be substituted by
one or more groups selected from among methyl, ethyl, iso-propyl,
tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
[0193] By the term "heteroaryl-C.sub.1-6-alkylene" (including those
which are part of other groups) are meant--even though they are
already included under "aryl-C.sub.1-6-alkylene"--branched and
unbranched alkylene groups with 1 to 6 carbon atoms, which are
substituted by a heteroaryl.
[0194] If not specifically defined otherwise, a heteroaryl of this
kind includes five- or six-membered heterocyclic aromatic groups or
5-10-membered, bicyclic heteroaryl rings which may contain one,
two, three or four heteroatoms selected from among oxygen, sulphur
and nitrogen, and contain so many conjugated double bonds that an
aromatic system is formed. The following are examples of five- or
six-membered heterocyclic aromatic groups or bicyclic heteroaryl
rings:
##STR00025##
[0195] Unless otherwise stated, these heteroaryls may be
substituted by one or more groups selected from among methyl,
ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine
and iodine.
[0196] The following are examples of
heteroaryl-C.sub.1-6-alkylenes:
##STR00026##
[0197] By the term "C.sub.1-6-haloalkyl" (including those which are
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 6 carbon atoms, which are substituted by one or
more halogen atoms. By the term "C.sub.1-4-alkyl" are meant
branched and unbranched alkyl groups with 1 to 4 carbon atoms,
which are substituted by one or more halogen atoms. Alkyl groups
with 1 to 4 carbon atoms are preferred. Examples include: CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3.
[0198] By the term "C.sub.3-7-cycloalkyl" (including those which
are part of other groups) are meant cyclic alkyl groups with 3 to 7
carbon atoms, if not specifically defined otherwise. Examples
include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may
be substituted by one or more groups selected from among methyl,
ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine
and iodine.
[0199] If not specifically defined otherwise, by the term
"C.sub.3-10-cycloalkyl" are also meant monocyclic alkyl groups with
3 to 7 carbon atoms and also bicyclic alkyl groups with 7 to 10
carbon atoms, or monocyclic alkyl groups which are bridged by at
least one C.sub.1-3-carbon bridge.
[0200] By the term "heterocyclic rings" or "heterocycle" are meant,
unless stated otherwise, five-, six- or seven-membered, saturated,
partially saturated or unsaturated heterocyclic rings which may
contain one, two or three heteroatoms, selected from among oxygen,
sulphur and nitrogen, while the ring may be linked to the molecule
through a carbon atom or through a nitrogen atom, if there is one.
Although included by the term "heterocyclic rings" or
"heterocycles", the term "saturated heterocyclic ring" refers to
five-, six- or seven-membered saturated rings. Examples
include:
##STR00027##
[0201] Although included by the term "heterocyclic rings" or
"heterocyclic group", the term "partially saturated heterocyclic
group" refers to five-, six- or seven-membered partially saturated
rings which contain one or two double bonds, without so many double
bonds being produced that an aromatic system is formed, unless
specifically defined otherwise. Examples include:
##STR00028##
[0202] Although included by the term "heterocyclic rings" or
"heterocycles", the term "heterocyclic aromatic rings" ,
"unsaturated heterocyclic group" or "heteroaryl" refers to five- or
six-membered heterocyclic aromatic groups or 5-10-membered,
bicyclic heteroaryl rings which may contain one, two, three or four
heteroatoms, selected from among oxygen, sulphur and nitrogen, and
contain so many conjugated double bonds that an aromatic system is
formed, unless not specifically defined otherwise. Examples of
five- or six-membered heterocyclic aromatic groups include:
##STR00029##
[0203] Unless otherwise mentioned, a heterocyclic ring (or
heterocycle) may be provided with a keto group. Examples
include:
##STR00030##
[0204] Although covered by the term "cycloalkyl", the term
"bicyclic cycloalkyls" generally denotes eight-, nine- or
ten-membered bicyclic carbon rings. Examples include
##STR00031##
[0205] Although already included by the term "heterocycle", the
term "bicyclic heterocycles" generally denotes eight-, nine- or
ten-membered bicyclic rings which may contain one or more
heteroatoms, preferably 1-4, more preferably 1-3, even more
preferably 1-2, particularly one heteroatom, selected from among
oxygen, sulphur and nitrogen, unless not specifically defined
otherwise. The ring may be linked to the molecule through a carbon
atom of the ring or through a nitrogen atom of the ring, if there
is one. Examples include:
##STR00032##
[0206] Although already included by the term "aryl", the term
"bicyclic aryl" denotes a 5-10 membered, bicyclic aryl ring which
contains sufficient conjugated double bonds to form an aromatic
system. One example of a bicyclic aryl is naphthyl.
[0207] Although already included under "heteroaryl", the term
"bicyclic heteroaryl" denotes a 5-10 membered, bicyclic heteroaryl
ring which may contain one, two, three or four heteroatoms,
selected from among oxygen, sulphur and nitrogen, and contains
sufficient conjugated double bonds to form an aromatic system,
unless specifically defined otherwise.
[0208] Although included by the term "bicyclic cycloalkyls" or
"bicyclic aryl", the term "fused cycloalkyl" or "fused aryl"
denotes bicyclic rings wherein the bridge separating the rings
denotes a direct single bond. The following are examples of a
fused, bicyclic cycloalkyl:
##STR00033##
[0209] Although included by the term "bicyclic heterocycles" or
"bicyclic heteroaryls", the term "fused bicyclic heterocycles" of
"fused bicyclic heteroaryls" denotes bicyclic 5-10 membered
heterorings which contain one, two, three or four heteroatoms,
selected from among oxygen, sulphur and nitrogen and wherein the
bridge separating the rings denotes a direct single bond. The
"fused bicyclic heteroaryls" moreover contain sufficient conjugated
double bonds to form an aromatic system. Examples include
pyrrolizine, indole, indolizine, isoindole, indazole, purine,
quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran,
benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine,
pteridine, pyrimidopyrimidine,
##STR00034##
[0210] "Halogen" within the scope of the present invention denotes
fluorine, chlorine, bromine or iodine. Unless stated to the
contrary, fluorine, chlorine and bromine are regarded as preferred
halogens.
[0211] Compounds of general formulas 1 or 1' may have acid groups,
mainly carboxyl groups, and/or basic groups such as e.g. amino
functions. Compounds of general formulas 1 or 1' may therefore be
present as internal salts, as salts with pharmaceutically usable
inorganic acids such as hydrochloric acid, sulphuric acid,
phosphoric acid, sulphonic acid or organic acids (such as for
example maleic acid, fumaric acid, citric acid, tartaric acid or
acetic acid) or as salts with pharmaceutically usable bases such as
alkali metal or alkaline earth metal hydroxides or carbonates, zinc
or ammonium hydroxides or organic amines such as e.g. diethylamine,
triethylamine, triethanolamine, inter alia.
[0212] As mentioned previously, the compounds of formulas 1 or 1'
may be converted into the salts thereof, particularly for
pharmaceutical use into the physiologically and pharmacologically
acceptable salts thereof. These salts may be present on the one
hand as physiologically and pharmacologically acceptable acid
addition salts of the compounds of formula 1 with inorganic or
organic acids. On the other hand, the compound of formulas 1 or 1'
when R is hydrogen may be converted by reaction with inorganic
bases into physiologically and pharmacologically acceptable salts
with alkali or alkaline earth metal cations as counter-ion. The
acid addition salts may be prepared for example using hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid,
lactic acid, citric acid, tartaric acid or maleic acid. It is also
possible to use mixtures of the above-mentioned acids. To prepare
the alkali and alkaline earth metal salts of the compounds of
formulas 1 or 1' wherein R denotes hydrogen, it is preferable to
use the alkali and alkaline earth metal hydroxides and hydrides, of
which the hydroxides and hydrides of the alkali metals,
particularly sodium and potassium, are preferred, while sodium and
potassium hydroxide are particularly preferred.
[0213] The compounds of general formulas 1 or 1' may optionally be
converted into the salts thereof, particularly for pharmaceutical
use into the pharmacologically acceptable acid addition salts with
an inorganic or organic acid. Examples of suitable acids for this
purpose include succinic acid, hydrobromic acid, acetic acid,
fumaric acid, maleic acid, methanesulphonic acid, lactic acid,
phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid
or citric acid. It is also possible to use mixtures of the
above-mentioned acids.
[0214] The invention relates to the compounds of formula 1 in
question, optionally in the form of the individual optical isomers,
mixtures of the individual enantiomers or racemates, in the form of
the tautomers as well as in the form of the free bases or the
corresponding acid addition salts with pharmacologically acceptable
acids--such as for example acid addition salts with hydrohalic
acids--for example hydrochloric or hydrobromic acid--or organic
acids--such as for example oxalic, fumaric, diglycolic or
methanesulphonic acid.
[0215] The compounds of formula 1, 1d, 1e or 1f according to the
invention may optionally be present as racemates, but may also be
obtained as pure enantiomers, i.e. in the (R) or (S) form.
Preferred are the compounds with the specific stereochemistry of
formula 1', in particular the compounds with the specific
stereochemistry of one of formulas 1d', 1e' or 1f'.
[0216] The invention relates to the compounds in question,
optionally in the form of the individual optical isomers,
diastereomers, mixtures of diastereomers, mixtures of the
individual enantiomers or racemates, in the form of the tautomers
as well as in the form of the free bases or the corresponding acid
addition salts with pharmacologically acceptable acids--such as for
example acid addition salts with hydrohalic acids--for example
hydrochloric or hydrobromic acid--or organic acids--such as for
example oxalic, fumaric, diglycolic or methanesulphonic acid.
[0217] The invention relates to the respective compounds of
formulas 1 or 1' in the form of the pharmacologically acceptable
salts thereof. These pharmacologically acceptable salts of the
compounds of formulas 1 or 1' may also be present in the form of
their respective hydrates (e.g. Monohydrates, dihydrates, etc.) as
well as in the form of their respective solvates.
[0218] By a hydrate of the compound according to the formulas 1 or
1' is meant, for the purposes of the invention, a crystalline salt
of the compound according to formulas 1 or 1', containing water of
crystallisation.
[0219] By a solvate of the compound according to formulas 1 or 1'
is meant, for the purposes of the invention, a crystalline salt of
the compound according to formulas 1 or 1', which contains solvent
molecules (e.g. Ethanol, methanol etc) in the crystal lattice.
[0220] The skilled man will be familiar with the standard methods
of obtaining hydrates and solvates (e.g. recrystallisation from the
corresponding solvent or from water).
4. METHODS OF PREPARATION
[0221] The Examples according to the invention were prepared as
shown in Schemes 1, 2 or 3.
##STR00035##
[0222] D is N, NH or CH,
[0223] G is C or N
[0224] T is C or N
[0225] E is C
[0226] Hal is Br or Cl
[0227] with X being --B(OH).sub.2, -boronic acid pinacolester,
-trifluoroborate or --SnBu.sub.3
[0228] PG is protecting group (e.g. benzyl, 1-phenylethyl,
1-(4-methoxyphenyl)ethyl)
[0229] and R.sup.1 is as herein before defined.
##STR00036##
[0230] D is CH, N or NH,
[0231] G is C or N
[0232] T is C or N
[0233] E is C
[0234] A is CH or N
[0235] Hal is Br or Cl
[0236] with X being --B(OH).sub.2, -boronic acid pinacolester,
-trifluoroborate or --SnBu.sub.3
[0237] PG is protecting group (e.g. benzyl, 1-phenylethyl,
1-(4-methoxyphenyl)ethyl)
[0238] and R.sup.1 is as herein before defined.
##STR00037##
[0239] 4.1. Starting materials of formula 2, 3, 4, 5 and 10
[0240] 4.1.1. Synthesis of Lactams 2 from Scheme 1, 2 and 3
[0241] Synthesis of Synthesis of
(R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-
-one 2.1 for Example 84 and
(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-
-one 2.2 for Examples 6 and 34.
Step 1: Synthesis of
(1'R,3R/S)-1-(1'-(4-Methoxyphenylethyl)-5-oxo-3-pyrrolidine
carboxylic acid (mixture of diastereoisomers)
##STR00038##
[0243] A suspension of 100 g of (R)-1-(4-methoxy-phenyl)-ethylamine
and 95 g itaconic acid in 0.5 L 1-methyl-2-pyrrolidinone was heated
to 80.degree. C. for 1 hour. The solution was stirred for
additional 4 hours at 120.degree. C. The reaction mixture was
cooled to 25.degree. C. and poured into 1.5 L of demineralized
water. The precipitate was filtered, washed with demineralized
water and dried at 50.degree. C.
[0244] Yield: 195 g (quantitative yield) solid as a mixture of
diastereoisomers
[0245] Analysis (method G): R.sub.t: 2.6 min and 2.7 min,
(M+H).sup.+: 264
Step 2: Synthesis of
(R/S)--N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-ca-
rboxamide as a mixture of diastereoisomers
##STR00039##
[0247] 260 g of 1,1'-carbonyldiimidazole (CD) were added to a
solution of 285 g
(1'R,3R/S)-1-(1'-(4-methoxyphenylethyl)-5-oxo-3-pyrrolidine
carboxylic acid (mixture of diastereoisomers) in 1.4 L
2-methyltetrahydrofuran at 20.degree. C. The suspension was stirred
at 20.degree. C. for 80 minutes. 235 mL ethyldiisopropylamine
(DIPEA) and 130 g of N,O-dimethylhydroxylamine hydrochloride were
added. The suspension was stirred for 3 hours at 20.degree. C.
Under cooling 850 mL 4M hydrochloric acid was added. The organic
phase was separated and washed two times with 500 mL 1 N
hydrochloric acid. The aqueous phase was reextracted two times with
500 mL ethyl acetate. The combined organic phases were dried over
sodium sulfate. After filtration the solvent was evaporated under
reduced pressure.
[0248] Yield: 271 g (82% of theory) of
(R/S)--N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-ca-
rboxamide (mixture of diastereoisomers) as an oil.
[0249] Analysis (method H): R.sub.t: 11.1 min (41 area %) and 13.8
min (59 area %), (M+H).sup.+: 307
Step 3: Synthesis of
(R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
as a Mixture of Diastereoisomers
##STR00040##
[0251] 530 mL of a 3M solution of methylmagnesium bromide in
diethylether were added slowly to a cooled solution of 271 g of
(R/S)--N-methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-ca-
rboxamide (mixture of diastereoisomers) in 1.4 L of
2-methyltetrahydrofuran so that the temperature remained under
0.degree. C. After complete addition the temperature was kept for
75 minutes at 0.degree. C. and then warmed up to 20.degree. C. The
suspension was stirred 16 hours at 20.degree. C. Under cooling 650
mL of a 4M hydrochloric acid were added. The organic phase was
separated and washed with 500 mL saturated sodium carbonate
solution and with 500 mL saturated brine. The organic phase was
dried over sodium sulfate. After filtration the solvent was
evaporated under reduced pressure.
[0252] Yield: 188 g (81% of theory) of
(R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
(mixture of diastereoisomers) as an oil.
[0253] Analysis (method H): R.sub.t: 7.4 min and 9.6 min,
(M+H).sup.+: 262
Step 4: Crystallization of
(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
Under Base Induced Epimerization Conditions
##STR00041##
[0255] 103 g of a mixture of diastereoisomers
(R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
were dissolved in 155 mL 1-butanol at 25.degree. C. 18 mL
benzyltrimethylammonium hydroxide (40% solution in methanol) was
added. The solution was stirred for 30 minutes at 25.degree. C. The
solution was cooled to 0.degree. C. Precipitation started. The
suspension was stirred for 15 minutes at 0.degree. C. 100 mL
n-heptane was added slowly and the suspension was stirred for 30
minutes at 0.degree. C. The addition of 100 mL portions of
n-heptane was repeated 4 times with subsequent stirring of the
suspension at 0.degree. C. for 30 minutes. The precipitate was
isolated, washed with n-heptane and dried at 50.degree. C.
[0256] Yield: 77.1 g of a beige solid (75% of theory) with a
diastereoisomeric purity of .about.95: 5 (method H).
[0257] For further purification the crude product was dissolved in
310 mL 2-methyl-2-butanol at 40.degree. C. (temperature
<50.degree. C.). The solution was slowly cooled to 0.degree. C.
Precipitation started. At 0.degree. C. 385 mL of n-heptane were
added and the suspension was stirred for 1 hour. The precipitate
was filtrated, washed with n-heptane and dried at 50.degree. C.
[0258] Yield: 68.7 g (67% of theory) of a colorless solid with a
diastereoisomeric purity of >99:1.
[0259] Analysis (method H): R.sub.t: 6.8 min, (M+H).sup.+: 262
Step 4: Crystallization of
(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
Under Base Induced Epimerization Conditions
##STR00042##
[0261] 13.2 g of a mixture of diastereoisomers
(R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
were dissolved in 18 mL of 1-butanol at 25.degree. C. The solution
was cooled to 3.degree. C. and treated with 100mg of
(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one.
The resulting mixture was agitated for 15 min at 3.degree. C.; at
which point, 2.3 mL benzyltrimethylammonium hydroxide (40% solution
in methanol) were added. The solution was stirred for 30 minutes at
3.degree. C. 64 mL n-heptane was added slowly over 1 h at 0 to
3.degree. C. and the suspension was stirred for 60 minutes at
0.degree. C. The precipitate was isolated, washed with n-heptane
and dried at 30.degree. C.
[0262] Yield: 10.6 g of a beige solid (80% of theory) with a
diastereoisomeric purity of .about.98: 2 (method H).
[0263] Analysis (method H): R.sub.t: 6.8 min, (M+H).sup.+: 262
Step 5: Synthesis of
(R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-11-(4-methoxyphenyl)-ethyl]-pyrrolidin--
2-one 2.1
##STR00043##
[0265] 94.6 mg of dichloro
(pentamethylcyclopentadienyl)-iridium(III) dimer and 105 mg of
(S,S)--N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine
[(R,R)-TsDPEN] were dissolved in 20 mL of acetonitrile and
subsequently charged to a slurry of 50 g of
(R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
and 65 g of sodium formate in 500 mL of water at 25.degree. C. The
slurry was heated to 60.degree. C. and agitated at this temperature
while sparging with nitrogen for 3 h. The reaction was diluted at
60.degree. C. with 500 mL of isopropyl acetate and subsequently
cooled to ambient temperature. The layers were separated, and the
organic portion was washed twice with 300 mL of water. The organic
portion was concentrated to an oily solid. The residual material
was crystallized three times from ethyl acetate and hexanes
followed by drying in a vacuum oven with a nitrogen stream at
30.degree. C.
[0266] 25.4 g of a beige solid with a diastereomeric purity of
>99:1
Step 5: Synthesis of
(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-
-one 2.2
##STR00044##
[0268] 9.46 mg of dichloro
(pentamethylcyclopentadienyl)-iridium(III) dimer and 10.52 mg of
(R,R)--N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine
[(R,R)-TsDPEN]were dissolved in 1 mL of acetonitrile and
subsequently charged to a slurry of 5 g of
(R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one
and 6.5 g of sodium formate in 50 mL of water at 25.degree. C. The
slurry was heated to 60.degree. C. and agitated at this temperature
while sparging with nitrogen for 3 h. The reaction was diluted at
60.degree. C. with 50 mL of isopropyl acetate and subsequently
cooled to ambient temperature. The layers were separated, and the
organic portion was washed with 20 mL of water. The organic portion
was concentrated to an oil. The oil was dissolved in 8 mL of
isopropyl acetate at reflux. The solution was cooled to ambient
temperature wherein crystallization occurred. The mixture was
diluted dropwise with 10 mL of heptane at ambient temperature. The
mixture was agitated for 30 minutes. The solids were collected by
filtration, washed with a solution of 20 vol % isopropyl acetate in
heptane and dried in a vacuum oven with a nitrogen stream at
55.degree. C. 3.82 g of a beige solid with a diastereomeric purity
of 99:1
[0269] Analysis (method I): R.sub.t: 12.9 min, (M+H).sup.+: 264
Synthesis of
[(1S)-1-[(3R)-1-[(1S)-1-(4-Methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]eth-
yl]4-methylbenzenesulfonate 2.3 for Example 6
##STR00045##
[0271] To a mixture of 20.0 g of
(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-
-one 2.2, 21.67 g p-toluenesulfonyl chloride and 0.92 g
N,N-dimethylpyridin-4-amine was added 42 mL pyridine and 42 mL
dichloromethane (DCM). The resulting mixture was stirred at
34.degree. C. for 18 h under argon atmosphere. The reaction mixture
was diluted with isopropyl acetate and washed with water and 2M
hydrochloric acid. The combined organic phases were dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was taken up in isopropyl acetate and n-heptane. The precipitate
was filtered off, washed with n-heptane/isopropyl acetate and dried
to yield 19.83 g of
[(1S)-1-[(3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]eth-
yl] 4-methylbenzenesulfonate 2.3 as solid.
[0272] Analysis: HPLC-MS: R.sub.t=0.680 min (method J), M+H=418
[0273] 4.1.2. Synthesis of Boronic Acids, Boronic Esters, BF.sub.3
Borates and Stannanes with Formula 4
[0274] X.1.2.1. Synthesis of R.sup.1-Hal 3
Synthesis of 4-Bromo-1-tert-butyl-pyrazole 3.1 for Examples 6, 34
and 84
Step 1: Synthesis of 1-tert-Butyl-pyrazole
##STR00046##
[0276] To a stirred mixture of 34.48 g of
1,1,3,3-tetramethoxy-propane and 26.20 g tert.-butylhydrazine
hydrochloride in 230 mL ethanol was added 40.0 mL conc.
hydrochloric acid dropwise below 50.degree. C., then the mixture
was stirred under reflux for 2 h. The reaction mixture was diluted
with water. The solvent was almost removed by destillation and the
aqueous residue extracted with diethylether. The combined aqueous
phases were basified with 10N sodium hydroxide solution and
extracted with diethylether. The combined organic phases were
washed with saturated brine, dried over sodium sulfate, filtered
and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole
as oil.
[0277] Analysis: HPLC-MS: R.sub.t=0.412 min (method A), M+H=125
Step 2: Synthesis of 4-Bromo-1-tert-butyl-pyrazole
##STR00047##
[0279] To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 mL
DCM was added 31.5 g N-bromosuccinimide in portions between 0 and
10.degree. C. The resulting mixture was stirred for 30 min. The
reaction mixture was allowed to reach ambient temperature. The
precipitate was filtered off and washed with DCM. The combined
organic extracts were washed with water and saturated brine, dried
over magnesium sulfate, filtered and concentrated in vacuo to yield
34.0 g of 4-bromo-1-tert-butyl-pyrazole as oil.
[0280] Analysis: HPLC-MS: R.sub.t=1.35 min (method B),
M+H=203/205
[0281] 4.1.3. Synthesis of Compounds of Formula 4 (R.sup.1--X)
(Scheme 1 and 2)
Synthesis of
1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
4.19 for Examples, 6, 34 and 84
##STR00048##
[0283] To a stirred mixture of 50 g of
4-bromo-1-tert-butyl-pyrazole 3.1 in 230 mL THF was added dropwise
100 mL 2.5M N-butyllithium solution in hexane under argon
atmosphere below -60.degree. C., then the mixture was stirred at
this temperature for 5 min, before 52 mL
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were added
dropwise below -60.degree. C. The reaction mixture was allowed to
reach ambient temperature. The mixture was cooled with an ice bath
and diluted with aqueous phosphate buffer solution and water and
neutralized with 2M aqueous hydrochloric acid. The organic solvent
was removed by destillation and the residue was extracted with DCM.
The combined organic extracts were washed with saturated brine,
dried over sodium sulfate, filtered and concentrated in vacuo to
yield 44.26 g of
1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
as solid.
[0284] Analysis: HPLC-MS: R.sub.t=0.904 min (method F), M+H=251
[0285] 4.1.4. Synthesis of Heterocyclic 5 and 10 from Scheme 1 and
2
Synthesis of 5,7-Dichloro-2-methyl[1,2,4]triazolo[1,5-c]pyrimidine
(5.2) for Example 84
[0286] 5.2 was synthesized according to WO 2008113469.
Step 1: Synthesis of
(6-Chloro-2-methylsulfanyl-pyrimidin-4-yl)-hydrazine
##STR00049##
[0288] A solution of 10.0 g
4,6-dichloro-2-methylsulfanyl-pyrimidine and 10.1 mL hydrazine
monohydrate in 40 mL DCM was stirred at 0.degree. C. overnight and
at room temperature for 2 days. The precipitate was filtered off,
washed with DCM and dried to afford 10.0 g of
(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-hydrazine as solid.
[0289] Analysis: HPLC-MS: R.sub.t=0.30 min (method J), M+H=191
Step 2: Synthesis of
7-Chloro-2-methyl-5-methylsulfanyl41,2,4]triazolo[1,5-c]pyrimidine
##STR00050##
[0291] A solution of 2.35 g
(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-hydrazine in 12 mL
triethyl orthoacetate and 10.7 mL glacial acid was refluxed for 1
h. The solvent was removed by destillation and the residue was
purified by rpHPLC (XbridgeC18, acetonitrile/water, ammonia) to
yield after lyophilisation 870 mg
7-chloro-2-methyl-5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidin-
e as solid.
[0292] Analysis: HPLC-MS: R.sub.t=0.40 min (method C), M+H=215
Step 3: Synthesis of
7-Chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ol
##STR00051##
[0294] To a solution of 1.67 g of
7-chloro-2-methyl-5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidine
in 35 mL methanol was added 3.13 mL aqueous potassium hydroxide
solution (40%), then the mixture was stirred at room temperature
for 10 min. The solvent was removed by destillation. The residue
was taken up in water and a neutral pH was adjusted with 4M aqueous
hydrochloric acid. The precipitate was filtered off, washed with
water and dried to yield 1.25 g of
7-chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ol as
solid.
[0295] Analysis: HPLC-MS: R.sub.t=0.23 min (method J), M+H=185
Step 4: Synthesis of
5,7-Dichloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidine (8.2)
##STR00052##
[0297] A mixture of 600 mg
7-chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ol and 103.5
.mu.L N,N-diethylaniline in 19.15 mL phosphorus oxychloride was
stirred at 100.degree. C. for 2 h. The solvent was removed by
destillation and the residue taken up in water. A neutral pH was
adjusted with saturated aqueous sodium bicarbonate solution and
aqueous phosphate buffer solution. The precipitate was filtered
off, washed with water and triturated with diethyl ether and
petroleum to yield 504 mg of
5,7-dichloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidine 5.2 as
solid.
[0298] Analysis: HPLC-MS: R.sub.t=0.403 min (method J), M+H=203
Synthesis of 6-Bromo-2-methyl-pyrazolo[1,5-a]pyridin-4-ol 10.3 for
Example 34
Step 1: Synthesis of
2,4-dinitro-phenolatel-amino-3-bromo-5-methoxy-pyridinium
##STR00053##
[0300] A mixture of 3.0 g of 3-bromo-5-methoxy-pyridine and 3.34 g
of O-(2,4-dinitro-phenyl)-hydroxylamine in 40 mL acetonitrile was
stirred at 50.degree. C. for 2 days, then at 80.degree. C. for 4 h.
The reaction mixture was allowed to reach ambient temperature and
diluted with TBME. The precipitate was filtered off, washed with
TBME and dried to yield 4.24 g of
2,4-dinitro-phenolatel-amino-3-bromo-5-methoxy-pyridinium as
solid.
[0301] Analysis: .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.7
(t, J=1.3 Hz, 1H), 8.63-8.55 (m, 2H), 8.44-7.99 (m, 3H), 7.76 (dd,
J=9.8, 3.2 Hz, 1H), 6.30 (d, J=9.8 Hz, 1H), 3.97 (s, 3H).
Step 2: Synthesis of
6-Bromo-4-methoxy-2-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic
acid methyl ester
##STR00054##
[0303] To a mixture of 4.24 g of
2,4-dinitro-phenolatel-amino-3-bromo-5-methoxy-pyridinium and 3.02
g potassium carbonate in 42.4 mL DMF was added 1.49 mL but-2-ynoic
acid methyl ester. The reaction mixture was stirred at 45.degree.
C. for 18 h. The reaction mixture was allowed to reach ambient
temperature, then diluted with water and extracted with ethyl
acetate/heptane (1:1). The combined organic phases were dried over
sodium sulfate, filtered and concentrated in vacuo. The crude
material was purified by flash chromatography (heptane/TBME/ethyl
acetate) to give 1.95 g of
6-bromo-4-methoxy-2-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic
acid methyl ester as solid.
[0304] Analysis: HPLC-MS: R.sub.t=2.94 min (method R),
M+H=299/301
Step 3: Synthesis of 6-Bromo-2-methyl-pyrazolo[1,5-a]pyridin-4-ol
10.3
##STR00055##
[0306] A mixture of 2.34 g of
6-bromo-4-methoxy-2-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic
acid methyl ester in 3.51 mL hydrogen bromide (48% aqueous) was
stirred in a sealed tube at 150.degree. C. for 8 h. The reaction
mixture was allowed to reach ambient temperature then diluted with
water. The mixture was worked up by adding saturated aqueous sodium
bicarbonate solution, followed by extraction with ethyl acetate.
The combined organic phases were dried over sodium sulfate,
filtered and concentrated in vacuo. The crude material was purified
by flash chromatography (heptane/ethyl acetate/methanol) to give
1.54 g (73% per HPLC) of
6-bromo-2-methyl-pyrazolo[1,5-a]pyridin-4-ol 10.3 as solid.
[0307] Analysis: HPLC-MS: R.sub.t=1.63 min (method K),
M+H=227/229
[0308] 4.2. Synthesis of Intermediates 6, 7, 8 and 11 from Scheme 1
and 2
Synthesis of
(4R)-4-[(1R)-1-[(7-Chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)o-
xy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 6.2 for
Example 84
##STR00056##
[0310] To a mixture of 537 mg
(R)-4-[(R)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-
-one 2.1 in 7.5 mL DMA was added 49 mg NaH at room temperature. The
resulting mixture was stirred at room temperature for 10 min,
before 414 mg
5,7-dichloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidine 5.2 were
added. The resulting mixtures was stirred at room temperature for 2
h and at 40.degree. C. for 2 h. Additional 49 mg NaH were added and
the reaction mixture was stirred at 40.degree. C. for 2 h. The
reaction mixture was quenched with saturated ammonium chloride
solution and extracted with DCM. The combined organic phases were
dried over magnesium sulfate, filtered and concentrated in vacuo.
The crude material was purified by rpHPLC (XbridgeC18,
acetonitrile/water, ammonia) to yield after lyophilisation 251 mg
of
(4R)-4-[(1R)-1-[(7-chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)o-
xy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 6.2 as
solid.
[0311] Analysis: HPLC-MS: R.sub.t=0.55 min (method C), M+H=430
Synthesis of
(4R)-4-[(1R)-1-(6-bromo-2-methyl-pyrazolo[1,5-a]pyridin-4-yl)oxyethyl]
pyrrolidin-2-one (7.6) for Example 34
##STR00057##
[0313] This intermediate was prepared from
6-bromo-2-methyl-pyrazolo[1,5-a]pyridin-4-ol 10.3 in two steps
according to the preparation of (4R)-4-[(1
R)-1-(6-bromo-2-methyl-indazol-4-yl)poxyethyl]pyrrolidin-2-one
7.5.
[0314] Analysis: HPLC-MS: R.sub.t=1.67 min (method K),
M+H=338/340
[0315] 4.3 Synthesis of the patent Examples of Formula 1
Synthesis of
(4R)-4-[(1R)-1-[[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-1H-benzimidazol-4--
yl]oxy]ethyl]pyrrolidin-2-one (Example 6)
Step 1: Synthesis of
1-Benzyl-4-benzyloxy-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazole
##STR00058##
[0317] To a mixture of 730 mg
1-benzyl-4-benzyloxy-6-bromo-2-methyl-benzimidazole, 538 mg
1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) and
146 mg 1,1'-bis(diphenylphospino)ferrocenedichloropalladium(II)
(complex with DCM (1:1)) in dioxane was added 2.69 mL 2M aqueous
sodium carbonat solution. The reaction mixture was stirred at
120.degree. C. for 30 min under microwave irradiation, then
filtered through Agilent PL-Thiol MP-SPE resin and washed with
methanol. The solvent was removed by destillation and the residue
was taken up in DCM and washed with water. The combined organic
phases were concentrated in vacuo. The resulting residue was
dissolved in acetonitrile/methanol, filtered through rp-SiO.sub.2,
washed with MeOH. The solvent was removed by destillation and the
residue was purified by rpHPLC (XbridgeC18, acetonitrile/water,
ammonia) to yield after lyophilisation 217 mg of
1-benzyl-4-benzyloxy-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazole
as solid.
[0318] Analysis: HPLC-MS: R.sub.t=0.76 min (method A), M+H=451
Step 2: Synthesis of
1-Benzyl-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazol-4-ol
##STR00059##
[0320] A mixture of 200 mg
1-benzyl-4-benzyloxy-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazole
and 200 mg palladium on carbon in 5 mL ethyl acetate was
hydrogenated at room temperature for 7 h at 1.01 bar. The catalyst
was removed by filtration and the solvent was evaporated in vacuo
to yield 160 mg (90% per HPLC)
1-benzyl-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazol-4-o- l
as solid.
[0321] Analysis: HPLC-MS: R.sub.t=0.99 min (method L), M+H=361
Step 3: Synthesis of
(4R)-4-[(1R)-141-Benzyl-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazo-
l-4-yl]
oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one
##STR00060##
[0323] A mixture of 130 mg
1-benzyl-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidazol-4-ol,
166 mg
[(1S)-1-[(3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]eth-
yl] 4-methyl-benzenesulfonate 2.3 and 150 mg potassium carbonate in
2 mL DMF was stirred at 60.degree. C. for 16 h. The reaction
mixture was allowed to reach ambient temperature, diluted with
water and extracted with ethyl acetate. The combined organic
extracts were washed with saturated brine, dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue was
purified by rpHPLC (XbridgeC18, acetonitrile/water, ammonia) to
yield after lyophilisation 42 mg of
(4R)-4-[(1R)-1-[1-benzyl-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidaz-
ol-4-yl]oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one
as solid.
[0324] Analysis: HPLC-MS: R.sub.t=1.30 min (method L), M+H=606
Step 4: Synthesis of
(4R)-4-[(1R)-1-[[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-1H-benzimidazol-4--
yl]
oxy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one
##STR00061##
[0326] A mixture of 42 mg
(4R)-4-[(1R)-1-[1-benzyl-6-(1-tert-butylpyrazol-4-yl)-2-methyl-benzimidaz-
ol-4-yl]oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one,
42 mg palladium on carbon and 140 .mu.L glacial acetic acid in 3 mL
ethanol was hydrogenated at room temperature for 5.5 h at 1 bar.
The catalyst was removed by filtration and the solvent was
evaporated in vacuo to yield 14 mg
(4R)-4-[(1R)-1-[[6-(1-tert-butylpyrazol-4-yl)-2-methyl-1H-benzimidazol-
-4-yl]oxy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one.
[0327] Analysis: HPLC-MS: R.sub.t=0.86 min (method F), M+H=516
Step 5: Synthesis of
(4R)-4-[(1R)-1-[[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-1H-benzimidazol-4--
yl]oxy]ethyl]pyrrolidin-2-one (Example 6)
##STR00062##
[0329] A mixture of 14 mg
(4R)-4-[(1R)-1-[[6-(1-tert-butylpyrazol-4-yl)-2-methyl-1H-benzimidazol-4--
yl]oxy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one in
200 .mu.L TFA was stirred at 70.degree. C. for 5 h. The reaction
mixture was diluted with methanol, filtered and purified by rpHPLC
(SunfireC18, acetonitrile/water, TFA) to yield after lyophilisation
7 mg of Example 6 as solid.
[0330] Analysis: HPLC-MS: R.sub.t=0.425 min (method S), M+H=382
Synthesis of
(4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[1,5-a]pyri-
din-4-yl]oxyethyl]pyrrolidin-2-one (Example 34)
##STR00063##
[0332] To a mixture of 100 mg
(4R)-4-[(1R)-1-(6-bromo-2-methyl-pyrazolo[1,5-a]pyridin-4-yl)oxyethyl]pyr-
rolidin-2-one 7.6, 111 mg
1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
4.19 and 10.4 mg 1,1'-bis(triphenylphosphine)palladium(II) chloride
in 1.50 mL ethanol (80% with toluene) was added 443 .mu.L 2M
aqueous sodium carbonat solution. The resulting mixture was stirred
at 95.degree. C. for 1 h. The reaction mixture was diluted with
water and extracted with DCM. The combined organic phases were
concentrated in vacuo. The crude residue was purified by flash
chromatography (heptane/ethyl acetate/methanol) and by rpHPLC to
yield 73 mg (yield: 65%) of Example 34.
[0333] Analysis: HPLC-MS: R.sub.t=2.63 min (method R), M+H=382
[0334] .sup.1H NMR (DMSO, 500 MHz) .quadrature.=1.29 (3H, d, J=6.1
Hz), 1.55 (9H, s), 2.16-2.33 (2H, m), 2.34 (3H, s), 2.75 (1H, h,
J=8.0 Hz), 3.10 (1H, dd, J=9.7, 6.5 Hz), 3.38 (1H, t, J=9.1 Hz),
4.77 (1H, p, J=5.9 Hz), 6.31 (1H, s), 6.91 (1H, s), 7.58 (1H, s),
7.96 (1H, s), 8.35 (1H, s), 8.50 (1H, s)
Synthesis of
(4R)-4-[(1R)-1-[[7-(1-tert-Butylpyrazol-4-yl)-2-methyl-[1,2,4]triazolo[1,-
5-c]pyrimidin-5-yl]oxy]ethyl]pyrrolidin-2-one (Example 84)
Step 1: Synthesis of
(4R)-4-[(1R)-1-[[7-(1-tert-butylpyrazol-4-yl)-2-methyl-[1,2,4]triazolo[1,-
5-c]pyrimidin-5-yl]oxy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin--
2-one
##STR00064##
[0336] A mixture of 80 mg
(4R)-4-[(1R)-1-[(7-chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)o-
xy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 7.2, 56
mg 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
4.19, 15.2 mg 1,1'-bis(diphenyl-phospino)
ferrocenedichloropalladium(II) (complex with DCM (1:1)) and 280
.mu.L 2M aqueous sodium carbonat solution in 1 mL dioxane was
stirred at 120.degree. C. for 25 min under microwave irradiation.
Additional 14 mg
1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were
added and the reaction mixture was stirred at 120.degree. C. for 10
min under microwave irradiation. The reaction mixture was filtered
through Agilent PL-Thiol MP-SPE, washed with methanol and purified
by rpHPLC (XbridgeC18, acetonitrile/water, ammonia) to yield after
lyophilisation 82 mg of
(4R)-4-[(1R)-1-[[7-(1-tert-butylpyrazol-4-yl)-2-methyl-[1,2,4]triazolo[1,-
5-c]pyrimidin-5-yl]oxy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin--
2-one 8.2 as oil.
[0337] Analysis: HPLC-MS: R.sub.t=0.60 min (method C), M+H=518
Step 2: Synthesis of
(4R)-4-[(1R)-1-[[7-(1-tert-Butylpyrazol-4-yl)-2-methyl-[1,2,4]triazolo[1,-
5-c]pyrimidin-5-yl]oxy]ethyl]pyrrolidin-2-one (Example 84)
##STR00065##
[0339] A mixture of 89 mg of
(4R)-4-[(1R)-1-[[7-(1-tert-butylpyrazol-4-yl)-2-methyl-[1,2,4]triazolo[1,-
5-c]pyrimidin-5-yl]oxy]ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin--
2-one 8.2 and 319 .mu.L anisole in 1.13 mL TFA was stirred at
80.degree. C. for 2.25 h. The reaction mixture was filtered and
purified by rpHPLC to yield after lyophilisation 31 mg of Example
84 as solid.
[0340] Analysis: HPLC-MS: R.sub.t=0.42 min (method X), M+H=384
[0341] 4.5 Analytical Methods
[0342] The Example compounds prepared according to the foregoing
synthesis schemes were characterised by the following
chromatographic methods and/or NMR spectroscopy.
[0343] 4.5.1 Chromatographic Methods (HPLC-MS Methods)
[0344] Method A
TABLE-US-00001 Column: Xbridge BEH C18, 2.1 .times. 30 mm, 1.7
.mu.m Column supplier: Waters Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H.sub.2O, 0.1% NH ] [Acetonitril] [ml/min]
[.degree. C.] 0.00 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60
1.10 0 100 1.3 60
[0345] Method B:
TABLE-US-00002 Column: Sunfire C18, 3 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 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
[0346] Method C:
TABLE-US-00003 Column: Xbridge BEH C18, 2.1 .times. 30 mm, 1.7
.mu.m Column supplier: Waters Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H.sub.2O, 0.1% NH.sub.3] [Acetonitril] [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
[0347] Method D:
TABLE-US-00004 Column: XBridge C18, 2.1 .times. 20 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 0.10% TFA] [Methanol] [ml/min] [.degree. C.] 0.0
95 5 1.4 60 0.05 95 5 1.4 60 1.00 0 100 1.4 60 1.1 0 100 1.4 60
[0348] Method E:
TABLE-US-00005 Column: Sunfire C18, 2.1 .times. 20 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 0.10% TFA] [Methanol] [ml/min] [.degree. C.] 0.00
99 1 1.3 60 0.15 99 1 1.3 60 1.10 0 100 1.3 60 1.25 0 100 1.3
60
[0349] Method F:
TABLE-US-00006 Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 0.1% NH.sub.3] [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
[0350] Method G:
TABLE-US-00007 Eluent A: Water/0.2% KH.sub.2PO.sub.4 pH = 3 Eluent
B: Acetonitrile Time [min] % A % B Flow rate [mL/min] 0.00 80 20
1.50 5.00 20 80 1.50 8.00 20 80 1.50
[0351] The stationary phase used was a Inertsil C8-3 (GL Sciences),
5 .mu.m; dimension: 100.times.4.0 mm,
[0352] (column temperature: constant at 30.degree. C.). Detection
UV 220 nm.
[0353] Method H:
TABLE-US-00008 Eluent A: Hexane Eluent B: 2-Propanol Time [min] % A
% B Flow rate [mL/min] 00.00 90 10 1.0 20.00 90 10 1.0
[0354] The stationary phase used was a Chiralpak AD-H (Daicel), 5
.mu.m; dimension: 150.times.4.6 mm,
[0355] (column temperature: constant at 10.degree. C.). Detection
DAD 225 nm.
[0356] Method I:
TABLE-US-00009 Eluent A: Hexane Eluent B: 2-Propanol Time [min] % A
% B Flow rate [mL/min] 00.00 90 10 1.0 25.00 90 10 1.0
[0357] The stationary phase used was a Chiralpak AD-H (Daicel), 5
.mu.m; dimension: 150.times.4.6 mm,
[0358] (column temperature: constant at 10.degree. C.).
[0359] Detection DAD 225 nm.
[0360] Method J:
TABLE-US-00010 Column: Sunfire C18, 2.1 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 0.1% TFA] [Acetonitril] [ml/min] [.degree. C.] 0.0
99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5
60
[0361] Method K:
[0362] Column: Waters Atlantis dC18 (2.1.times.50 mm, 3 .mu.m
column)
[0363] Flow rate: 1 mL/min
[0364] Solvent A: 0.1% Formic acid/water
[0365] Solvent B: 0.1% Formic acid/acetonitrile
[0366] Injection volume: 3 .mu.L
[0367] Column temperature: 40.degree. C.
[0368] UV Detection wavelength: 215 nm
[0369] Eluent: 0 to 2.5 minutes, constant gradient from 95% solvent
A+5% solvent B to 100% solvent B; 2.5 to 2.7 minutes, 100% solvent
B; 2.71 to 3.0 minutes, 95% solvent A+5% solvent B.
[0370] MS detection using Waters LCT Premier, QTof micro, ZQ or
Shimadzu LCMS2010EV
[0371] UV detection using Waters 2996 photodiode array, Waters 2998
photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA
[0372] Method L:
TABLE-US-00011 Column: XBridge C18, 4.6 .times. 30 mm, 3.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 0.1% NH.sub.3] [ACN] [ml/min] [.degree. C.] 0.0 97
3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60
[0373] Method M:
[0374] Column: Waters SymmetryShield RP8 (2.1.times.50 mm, 3.5
.mu.m column)
[0375] Flow rate: 1 mL/min
[0376] Solvent A: 0.1% Formic acid/water
[0377] Solvent B: 0.1% Formic acid/acetonitrile
[0378] Injection volume: 3 .mu.L
[0379] Column temperature: 40.degree. C.
[0380] UV Detection wavelength: 215 nm
[0381] Eluent: 0 to 2.2 minutes, constant gradient from 95% solvent
A +5% solvent B to 100% solvent B; 2.2 to 2.7 minutes, 100% solvent
B; 2.71 to 3.0 minutes, 95% solvent A+5% solvent B.
[0382] MS detection using Waters LCT Premier, QTof micro, ZQ or
Shimadzu LCMS2010EV
[0383] UV detection using Waters 2996 photodiode array, Waters 2998
photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA
[0384] Method N:
TABLE-US-00012 Column: Xbridge BEH C18, 2.1 .times. 30 mm, 1.7
.mu.m Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H.sub.2O, 0.1% TFA] [Acetonitril] [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
[0385] Method O:
TABLE-US-00013 Column: Xbridge BEH Phenyl, 2.1 .times. 30 mm, 1.7
.mu.m Column supplier: Waters Gradient/Solvent % Sol % Sol Flow
Temp Time [min] [H.sub.2O, 0.1% NH.sub.3] [Acetonitril] [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
[0386] Method P:
[0387] Column: Supelco Ascentis Express (2.1.times.30 mm, 2.7 .mu.m
column)
[0388] Flow rate: 1 ml/min
[0389] Solvent A: 0.1% Formic acid/water
[0390] Solvent B: 0.1% Formic acid/acetonitrile
[0391] Injection volume: 3 .mu.L
[0392] Column temperature: 40.degree. C.
[0393] UV Detection wavelength: 215 nm
[0394] Eluent: 0 to 1.5 minutes, constant gradient from 95% solvent
A+5% solvent B to 100% solvent B; 1.5 to 1.6 minutes, 100% solvent
B; 1.60 to 1.61 minutes, constant gradient from 100% solvent B to
95% solvent A+5% solvent B; 1.61 to 2.00 minutes, 95% solvent A+5%
solvent B.
[0395] MS detection using Waters LCT Premier, QTof micro, ZQ or
Shimadzu LCMS2010EV
[0396] UV detection using Waters 2996 photodiode array, Waters 2998
photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA
[0397] Method Q
[0398] Column: Atlantis d C18; 50.times.3 mm; 3 .mu.
[0399] Flow rate: 0.6 ml/min
[0400] Solvent A: 0.1% Formic acid in water
[0401] Solvent B: 0.1% Formic acid in acetonitrile
[0402] Injection Volume: 5 .mu.L
[0403] Column temperature: 35.degree. C.
[0404] UV Detection wavelength: Spectra A max (with scan in the
region of 200-400nm) Eluent: 0 to 3.5 minutes, constant gradient
from 95% solvent A+5% solvent B to 100% solvent B; 3.5 to 3.8
minutes, 100% solvent B; 3.8 to 3.9 minutes, constant gradient from
100% solvent B to 95% solvent A+5% solvent B; 3.9 to 4.5 minutes,
95% solvent A+5% solvent B.
[0405] MS detection using Waters 3100, SQ detector, ES +ve and -ve
modes (Cone voltage: 30V, Capillary voltage 3.0 KV)
[0406] UV detection using Waters 2996 photodiode array
[0407] Method R:
[0408] Column: Phenomenex Kinetex-XB C18 (2.1.times.100 mm, 1.7
.mu.m column)
[0409] Flow rate: 0.6 mL/min
[0410] Solvent A: 0.1% Formic acid/water
[0411] Solvent B: 0.1% Formic acid/acetonitrile
[0412] Injection volume: 3 .mu.L
[0413] Column temperature: 40.degree. C.
[0414] UV Detection wavelength: 215 nm
[0415] Eluent: 0 to 5.3 minutes, constant gradient from 95% solvent
A+5% solvent B to 100% solvent B; 5.3 to 5.8 minutes, 100% solvent
B; 5.80 to 5.82 minutes, constant gradient from 100% solvent B to
95% solvent A+5% solvent B; 5.82 to 7mins, 95% solvent A+5% solvent
B
[0416] MS detection using Waters SQD
[0417] UV detection using Waters Acquity photodiode array
[0418] Method S:
TABLE-US-00014 Column: Sunfire C18, 2.1 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/Solvent % Sol % Sol Flow Temp Time
[min] [H.sub.2O, 0.1% TFA] [Acetonitril] [ml/min] [.degree. C.] 0.0
99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3
60
[0419] Method T:
[0420] Column: Phenomenex Gemini C18 (2.0 mm.times.100 mm, 3 .mu.m
column)
[0421] Flow rate: 0.5 mL/min
[0422] Solvent A: 2 mM Ammonium bicarbonate modified to pH 10 with
Ammonium Hydroxide/water
[0423] Solvent B: Acetonitrile
[0424] Injection volume: 3 .mu.L
[0425] Column temperature: 40.degree. C.
[0426] UV Detection wavelength: 215 nm
[0427] Eluent: 0 to 5.5 minutes, constant gradient from 95% solvent
A+5% solvent B to 100% solvent B; 5.5 to 5.9 minutes, 100% solvent
B; 5.90 to 5.92 minutes, constant gradient from 100% solvent B to
95% solvent A+5% solvent B; 5.92 to 9.00 minutes, 95% solvent A+5%
solvent B.
[0428] Method U:
TABLE-US-00015 Column: XBridge C18_3.0 .times. 30 mm, 2.5 .mu.m
Column producer: Waters Description: Gradient/Solvent % Sol
[H.sub.2O % Sol Flow Temp Time [min] 0.1% NH.sub.4OH]
[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
[0429] Method V:
TABLE-US-00016 Column: XBridge C18_3.0 .times. 30 mm, 2.5 .mu.m
Column producer: Waters Gradient/Solvent % Sol [H.sub.2O % Sol Flow
Temp Time [min] 0.1% NH.sub.4OH] [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
[0430] Method W:
TABLE-US-00017 Column: Sunfire C18_3.0 .times. 30 mm, 2.5 .mu.m
Column producer: Waters Description: Gradient/Solvent % Sol
[H.sub.2O % Sol Flow Temp Time [min] 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
[0431] Method X:
TABLE-US-00018 Column: Sunfire C18_2.1 .times. 50 mm, 2.5 .mu.m
Column producer: Waters Description: Gradient/Solvent % Sol
[H.sub.2O % Sol [Acetonitrile Flow Temp Time [min] 0.1% TFA] 0.08%
TFA] [ml/min] [.degree. C.] 0.0 95.0 5.0 1.5 60.0 0.75 0.0 100.0
1.5 60.0 0.85 0.0 100.0 1.5 60.0
[0432] Method Y:
TABLE-US-00019 Device description: Waters Acquity with 3100 MS
Column: XBridge BEH C18_3.0 .times. 30 mm, 1.7 .mu.m Column
producer: Waters Description: Gradient/Solvent % Sol [H.sub.2O %
Sol Flow Temp Time [min] 0.1% NH.sub.4OH] [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
[0433] Method Z:
[0434] Column: Waters Atlantis dC18 (2.1.times.100 mm, 3 .mu.m
column)
[0435] Flow rate: 0.6 mL/min
[0436] Solvent A: 0.1% Formic acid/water
[0437] Solvent B: 0.1% Formic acid/acetonitrile
[0438] Injection Volume: 3 .mu.L
[0439] Column temperature: 40.degree. C.
[0440] UV Detection wavelength: 215 nm
[0441] Eluent: 0 to 5 minutes, constant gradient from 95% solvent A
+5% solvent B to 100% solvent B; 5 to 5.4 minutes, 100% solvent B;
5.4 to 5.42 minutes, constant gradient from 100% solvent B to 95%
solvent A+5% solvent B; 5.42 to 7.00 minutes, 95% solvent A+5%
solvent B.
[0442] MS detection using Waters LCT Premier, QTof micro, ZQ or
Shimadzu LCMS2010EV
[0443] UV detection using Waters 2996 photodiode array, Waters 2998
photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA
[0444] Method Z1:
TABLE-US-00020 Method Name: Method Name: Column: Sunfire, 3 .times.
30 mm, 2.5 .mu.m Column Supplier: Waters Gradient/Solvent % Sol %
Sol Flow Temp Time [min] [H.sub.2O, 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
[0445] 4.5.2 NMR Spectroscopy
[0446] Configuration of the Bruker DRX 500 MHz NMR
[0447] High performance digital NMR spectrometer, 2-channel
microbay console and Windows XP host workstation running Topspin
version 1.3.
[0448] Equipped with: [0449] Oxford instruments magnet 11.74 Tesla
(500 MHz proton resonance frequency) [0450] B-VT 3000 temperature
controller [0451] GRASP II gradient spectroscopy accessory for fast
acquisition of 2D pulse sequences [0452] Deuterium lock switch for
gradient shimming [0453] 5 mm Broad Band Inverse geometry double
resonance probe with automated tuning and matching (BBI ATMA).
Allows .sup.1H observation with pulsing/decoupling of nuclei in the
frequency range .sup.15N and .sup.31P with .sup.2H lock and
shielded z-gradient coils.
[0454] Configuration of the Bruker DPX 400 MHz NMR
[0455] High performance one bay Bruker 400 MHz digital two channel
NMR spectrometer console and Windows XP host workstation running
XwinNMR version 3.5.
[0456] Equipped with: [0457] Oxford instruments magnet 9.39 Tesla
(400 MHz proton resonance frequency) [0458] B-VT 3300 variable
temperature controller unit [0459] Four nucleus (QNP) switchable
probe for observation of .sup.1H, .sup.13C, .sup.19F and .sup.31P
with .sup.2H lock
[0460] Configuration of the Bruker 500 MHz NMR
[0461] High performance digital NMR spectrometer, 2-channel one bay
console and Linux host workstation running Topspin version 2.1
PL6.
[0462] Equipped with: [0463] Bruker-Biospin AVANCE III 500A magnet
11.75 Tesla (500 MHz proton resonance frequency) [0464] B-VT 3000
temperature controller [0465] 5 mm Multinuclear Broad Band fluorine
observe (BBFO) probe with digital tuning covering the range from
.sup.15N and .sup.31P as well as .sup.19F with .sup.1H
decoupling.
[0466] Configuration of the Bruker DPX 400 MHz NMR
[0467] High performance digital NMR spectrometer, 2-channel
microbay console and Linux host workstation running Topspin version
2.1 PL6
[0468] Equipped with: [0469] Bruker-Biospin AVANCE Ill DPX400C
magnet 9.40 Tesla (400 MHz proton resonance frequency) [0470] B-VT
3200 variable temperature controller unit
[0471] 5 mm Multinuclear Broad Band fluorine observe (BBFO) probe
with digital tuning covering the range from .sup.15N and .sup.31P
as well as .sup.19F with .sup.1H decoupling.
5. EXAMPLES
[0472] The following Examples were prepared analogously to the
methods of synthesis described above. These compounds are suitable
as SYK inhibitors and have IC.sub.50-values with regard to
SYK-inhibition of less than or equal to 1 pmol. Additionally these
compounds exhibit a very good SYK-selectivity which means
that--whereas SYK is inhibited effectively--other kinases such as
Aurora B (AURB), FLT-3 and GSK 3.beta. are not or almost not
inhibited at all. Consequently undesired side effects of these
effective SYK-inhibitors of the invention are minimized.
[0473] AURB phosphorylates Ser10 and Ser28 on histone H3, a key
event in mitosis and cellular proliferation. Inhibition of AURB
therefore has the potential to block cellular proliferation, and
could compromise tissues that exhibit a high cellular turnover,
such as the intestine or the bone marrow. It is therefore desired
to avoid parallel AURB inhibition of an effective SYK inhibitor to
improve the overall clinical safety profile of the compound.
Consequently all example compounds show IC.sub.50-values with
regard to Aurora B inhibition of more than 1 .mu.M, preferably more
than 6 .mu.M, more preferably more than 10 .mu.M, more preferably
more than 30 .mu.M, particularly preferably more than 50 .mu.M. The
AURB-IC.sub.50/SYK-IC.sub.50-ratios of all example compounds are
preferably more than 30, more preferably more than 100.
[0474] FLT-3 is a tyrosine kinase receptor. When an FLT-3 ligand
binds to the receptor, the intrinsic tyrosine kinase activity of
the receptor is activated, which in turn phosphorylates and
activates signal transduction molecules (such as SHC) which in turn
propagates the signal in the cell. Signaling through FLT-3 plays a
role in cell survival, proliferation, and differentiation and is
important for lymphocyte (B cell and T cell) development. It is
therefore desired to avoid parallel FLT-3 inhibition of an
effective SYK inhibitor to improve the overall clinical safety
profile of the compound. Consequently all example compounds of the
instant invention show IC.sub.50-values with regard to FLT-3
inhibition of more than 0.30 .mu.M, preferably more than 1 .mu.M,
more preferably more than 10 .mu.M, particularly preferably more
than 30 .mu.M. The FLT-3-IC.sub.50/SYK-IC.sub.50-ratios of all
example compounds are preferably more than 10, more preferably more
than 30.
[0475] Glycogen synthase kinase 3 beta (GSK 3.beta.) is a
proline-directed serine-threonine kinase that is prominent in the
TGF-.beta. and Wnt intracellular signalling pathways. GSK 3.beta.
facilitates a number of intracellular signalling pathways including
the activation of .beta.-catenin complex. In adults, GSK 3.beta. is
involved in cellular proliferation and energy metabolism, whilst in
neonates is involved in neuronal cell development and body pattern
formation. It is therefore desired to avoid parallel GSK3.beta.
inhibition of an effective SYK inhibitor to improve the overall
clinical safety profile of the compound. Consequently all example
compounds of the invention show IC.sub.50-values with regard to GSK
3.beta. inhibition of more than 1 .mu.M, preferably of more than 10
.mu.M.
[0476] Further it is desirable for an SYK-inhibitor to have certain
human liver microsomal stability (corresponding to CI<60%
Q.sub.h; % Q.sub.h=percentage of liver blood flow). Otherwise it
will be difficult to reach an adequate plasma level of the
SYK-inhibitor in the patient to be treated.
[0477] The IC.sub.50-values with respect to SYK-inhibition,with
respect to Aurora B inhibition,with respect to FLT3-inhibition and
with respect to GSKbeta-inhibition as well as the human liver
microsomal stablities (CI [% Q.sub.h]) for each of the individual
example substances are shown in the following Table 1 and were
experimentally determined as follows:
[0478] 5.1 Syk Kinase Test
[0479] Recombinant human Syk (amino acids 342-635) was expressed as
a fusion protein with an N-terminal GST tag, affinity-purified and
deep-frozen at a concentration of approx. 50-100 .mu.M in storage
buffer (25 mM HEPES pH7.5; 25 mM MgCl.sub.2; 5 mM MnCl.sub.2; 50 mM
KCl; 0.2% BSA; 0.01% CHAPS; 100 .mu.M Na.sub.3VO.sub.4; 0.5 mM DTT,
10% glycerol) at -80.degree. C. until use.
[0480] The catalytic activity of the GST-Syk kinase fusion protein
was determined using the Kinase Glo.RTM. Luminescence Kinase test
(Promega; V6712). In this homogeneous test the amount of ATP
remaining after the kinase reaction is quantified by a
luciferin-luciferase reaction using luminescence. The luminescence
signal obtained correlates with the amount of ATP still present and
thus correlates inversely with the activity of the kinase.
[0481] Method
[0482] The test compounds were dissolved in 100% DMSO at a
concentration of 10 mM and diluted in DMSO to a concentration of 1
mM. Serial Dilution is done in 100% DMSO. All further dilutions of
the substances were carried out with test buffer (25 mM HEPES
pH7.5; 25 mM MgCl.sub.2; 5 mM MnCl.sub.2; 50 mM KCl; 0.2% HSA;
0.01% CHAPS; 100 .mu.M Na.sub.3VO.sub.4; 0.5 mM DTT). Dilution
steps and concentration range were adapted according to need. 7 pl
aliquots of these dilutions were transferred into a 384-well
Optiplate (Perkin Elmer, #6007290). GST-Syk was diluted to 12 nM in
the test buffer and 5 .mu.l of this dilution were used in the
kinase test (final concentration of Syk=4 nM in a total volume of
15 .mu.l). After 15 minutes incubation at room temperature 3 .mu.l
of a mixture of 750 nM ATP and 100 .mu.g/ml poly (L-Glutamic acid
L-Tyrosine 4:1), Fluka #81357) in test buffer were added to each
well and the incubation was continued for a further 60 minutes at
room temperature.
[0483] Positive controls are the reaction mixtures that contain no
test substance; negative controls (blanks) are reaction mixtures
that contain no kinase.
[0484] After 60 minutes, 10 .mu.l Kinase-Glo.RTM. solution
(Promega, Cat. #V6712) (heated to room temperature) were added to
each well and incubation was continued for a further 15 minutes.
The plates were read in Envision Luminescence Reader
(Perkin-Elmer).
[0485] Data Evaluation and Calculation:
[0486] The output file of the reader is a csv file that contains
the well number and measured relative light units (RLU). For data
evaluation and calculation, the measurement of the negative control
was set as 100% ctrl and the measurement of the positive control
was set as 0% ctrl. Based on this values the % value for the
measurement of each substance concentration was calculated using an
Assay Explorer software (Accelrys). Normally, the % ctrl values
calculated are between 0% and 100% values but may also occur
outside these limits in individual cases based on variability or
compound characteristics. The IC.sub.50 values were calculated from
the % ctrl values using Assay Explorer software.
Calculation:[y=(a-d)/(1+(x/c) b)+d]a=low value, d=high value;
x=conc M; c=IC50 M; b=hill; y=% ctrl.
[0487] 5.2 Aurora B Kinase Test
[0488] Recombinant human Aurora B (amino acids 1-344, clone number
DU1773, Molecular weight 40.2 kDa, University of Dundee) was
expressed as a fusion protein with an N-terminal His tag,
affinity-purified and deep-frozen at a concentration of approx.
0.25-0.5 mg/ml in storage buffer (50 mM Tris-HCl pH 8; 25 mM
Na-.beta.-glycerophosphat; 0.1 mM EGTA; 150 mM NaCl; 0.03% Brij-35;
1 mM DTT and 10% glycerol) at -80.degree. C. until use.
[0489] The activity of the Aurora B kinase protein was determined
using the ADP Glo.RTM. Luminescence Kinase test (Promega; V9103X).
In this homogeneous test the amount of ADP remaining after the
kinase reaction is quantified by a luciferin-luciferase reaction
using luminescence. The luminescence signal obtained correlates
with the amount of ADP still present and thus correlates with the
activity of the protein kinase.
[0490] Method
[0491] The test compounds were dissolved in 100% DMSO at a
concentration of 10 mM and diluted in DMSO to a concentration of 5
mM. Serial Dilution is done in 1:10 steps in 100% DMSO. All further
dilutions of the substances were carried out with test buffer (50
mM Hepes, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 60 .mu.M Ultra Pure ATP,
0.01% Brij35, 0.1% BSA, 5 mM .beta.-Glycerophosphate) until a
concentration was reached which was 2.5 times above the final test
concentration (final concentration of the compounds: 50 .mu.M to
0.005 nM). 4 .mu.l aliquots of these dilutions were transferred
into a 384-well Optiplate (Perkin Elmer, #6007290). His-Aurora B
was diluted to 125 nM in the test buffer and 4 .mu.l of this
dilution were used in the kinase test (final concentration of
Aurora B=50 nM in a total volume of 10 .mu.l). After 15 minutes
incubation at room temperature 2 .mu.l of 250 .mu.M substrate
([LRRLSLGLRRLSLGLRRLSLGLRRLSLG]; University of Dundee) in test
buffer were added to each well and the incubation was continued for
a further 60 minutes at room temperature.
[0492] Positive controls are the reaction mixtures that contain no
test substance; negative controls (blanks) are reaction mixtures
that contain no kinase.
[0493] After 60 minutes, 10 .mu.l ADP-Glo.RTM. solution (ADP-Glo
Reagent #V912B Promega) (heated to room temperature) were added to
each well and incubation was continued for a further 40. minutes.
Then 20 .mu.l Kinase detection mix (Detection Buffer #V913B
Promega; Kinase Detection Substrate #V914B Promega) were added and
incubated for 40 minutes at room temperature. The plates were read
in Envision Luminescence Reader (Perkin-Elmer).
[0494] Data Evaluation and Calculation:
[0495] The output file of the reader is a csv file that contains
the well number and measured RLU. For data evaluation and
calculation, the measurement of the negative control was set as 0%
ctrl and the measurement of the positive control was set as 100%
ctrl. Based on this values the % value for the measurement of each
substance concentration was calculated using an Assay Explorer
software (Accelrys). Normally, the % ctrl values calculated are
between 0% and 100% values but may also occur outside these limits
in individual cases based on variability or compound
characteristics. The IC.sub.50 values were calculated from the %
ctrl values using Assay Explorer software.Calculation:
[y=(a-d)/(1+(x/c) b)+d], a=low value, d=high value; x=conc M;
c=IC50 M; b=hill; y=% ctrl.
[0496] 5.3 FLT3 Kinase Test
[0497] FLT3 is obtained from Invitrogen in 50 mM Tris (pH7.5); 100
mM NaCl; 0.05 mM EDTA, 0.05% NP-40, 2 mM DTT; 50% Glycerol #PV3182;
Lot 286671; sequence see below). The enzyme is diluted to 720 nM
(35 .mu.g/ml) in enzyme dilution buffer and 10 .mu.l aliquots are
stored at -80.degree. C.
[0498] The activity of FLT3 is measured using the Z'-LYTETM assay
technology from Invitrogen (#PV3191)
[0499] Method
[0500] The assay is performed in 384 black plates from Corning
(#3676) in a final volume of 10 .mu.l by adding 5 .mu.l of kinase
peptide mix and 2.5 .mu.l of compound dilution. The reaction is
started by addition of 2.5 .mu.l of the 4.times.]ATP solution.
[0501] Final concentration in assay: FLT3 2 nM, Tyr2 peptide 4
.mu.M, ATP 470 .mu.M (ATP Km for FLT3)
[0502] Positive controls are reaction mixtures containing no test
compound; negative controls (blanks) are reaction mixtures
containing no kinase. As a further control, the phosphopeptide
solution is added to wells without kinase(=100% phosphorylation
control). The non inhibited kinase reaction will result in a
phosphorylation corresponding to 20%-30% of the phosphorylation
control.
[0503] The reaction is performed for 1 h at room temperature before
5 .mu.l of the development solution is added. After a further
incubation for 1 h at room temperature 5 .mu.l of the stop reagent
is added. The plates are read on a Flex Station II 384 (Molecular
Devices).
[0504] To control for any potential inhibition of the protease
present in the development solution, the phosphopeptide is
incubated with the development solution in the presence of the
highest concentration of the test compound (usually 100 .mu.M or 10
.mu.M).
[0505] Data Evaluation and Calculation:
[0506] The output text file is evaluated in an "MS-Excel-VB-Makro"
and "GraphPadPrism"(Version 5) (GraphPad Software Inc.) is used to
calculate the results. Data for the inhibition of FLT3 are reported
in M. data for the inhibition of the protease are reported in %
CTL.
[0507] 5.4 GSK 3.beta. Kinase-Test
[0508] Human GSK3beta (expressed and purified from SF21 cells)is
obtained from the University Dundee/Scotland (Dr. James
Hastie--Dept. of Biochemistry) in 50 mM Tris (pH7.5); 150 mM NaCl;
0.1 mM EGTA, 270 mM Succrose, 0.1% R-mercaptoethanol, 1 mM
benzamidine, 0.2 mM PMSF; sequence see below). The enzyme is
diluted to 3.56 .mu.M (168 .mu.g/ml) in enzyme dilution buffer and
6 .mu.l aliquots are stored at -80.degree. C.
[0509] The activity of GSK3.beta. kinase protein is measured using
the Z'-LYTETM assay technology from Invitrogen (#PV3324).
[0510] Method:
[0511] The assay is performed in 384 black plates from Corning
(#3676) in a final volume of 10 .mu.l by adding 5 .mu.l of kinase
peptide mix and 2.5 .mu.l of compound dilution. The reaction is
started by addition of 2.5 .mu.l of the 4.times. ATP solution.
[0512] Final concentration in assay: GSK3.beta. 5 nM, Ser/Thr9
peptide 2 .mu.M, ATP 7 .mu.M (ATP Km for GSK3.beta.)
[0513] Positive controls are reaction mixtures containing no test
compound; negative controls (blanks) are reaction mixtures
containing no ATP. As a further control, the phosphopeptide
solution is added to wells without kinase and without ATP(=100%
phosphorylation control). The non inhibited kinase reaction will
result in a phosphorylation corresponding to 20%-30% of the
phosphorylation control.
[0514] The reaction is performed 1 h at room temperature. After 1 h
5 .mu.l of the development solution is added. After a further
incubation for 1 h at room temperature 5 .mu.l of the stop reagent
is added. Finally the plates are read on a Flex Station II 384
(Molecular Devices).
[0515] To control for any potential inhibition of the protease
present in the development solution, the phosphopeptide is
incubated with the development solution in the presence of the
highest concentration of the test compound (usually 100 .mu.M).
[0516] Data Evaluation and Calculation:
[0517] The output text file is evaluated in an "MS-Excel-VB-Makro"
and "Graph Pad Prism"(Version 5) (GraphPad Software Inc.) is used
to calculate the results. Data for the inhibition of GSK3beta are
reported in M. data for the inhibition of the protease are reported
in % CTL.
[0518] 5.5 Human Liver Microsomal Stability Test
[0519] Further it is desirable for an SYK-inhibitor that is
sufficiently SYK-specific as described above to have certain human
liver microsomal stability (corresponding to CI<60% Q.sub.h; %
Q.sub.h=percentage of liver blood flow). Otherwise it will be
difficult to reach an adequate plasma level of the SYK-inhibitor in
the patient to be treated.
[0520] Method:
[0521] The metabolic degradation for a specific SYK-inhibitor is
performed at 37.degree. C. with pooled human liver microsomes
(human liver microsomes are commercially available as "BD
UltraPool.TM." by Corning Life Sciences, Fogostraat 12, 1060 LJ
Amsterdam, The Netherlands). The final incubation volume of 100
.mu.l per time point contains TRIS buffer pH 7.6 at RT (0.1 M),
magnesium chloride (5 mM), microsomal protein (1 mg/ml) and the
test compound at a final concentration of 1 .mu.M.
[0522] Following a short preincubation period at 37.degree. C., the
reaction is initiated by addition of beta-nicotinamide adenine
dinucleotide phosphate in its reduced form (NADPH, 1 mM) and
terminated by transfering an aliquot into solvent after different
time points. Additionally, the NADPH-independent degradation is
monitored in incubations without NADPH, terminated at the last time
point.
[0523] The quenched (terminated) incubations are then pelleted by
centrifugation (10000 g, 5 min).
[0524] An aliquot of the supernatant is assayed by LC-MS/MS for the
remaining amount of parent compound. The half-life (t1/2 INVITRO)
is determined by the slope of the semilogarithmic plot of the
concentration-time profile.
[0525] Data Evaluation and Calculation:
[0526] The intrinsic clearance (CL_INTRINSIC) is calculated by
considering the amount of protein in the incubation:
CL_INTRINSIC [.mu.l/min/mg protein]=(Ln 2/(t1/2 INVITRO [min] *
protein content [mg/ml]))*1000
[0527] The protein content [mg/ml] was determined with the
"Bicinchoninic Acid Kit" of Sigma Aldrich (commercially
available).
[0528] The upscaled intrinsic Clearance (CL_UP_INT) is calculated
by considering the liver weight [g liver/kg body weight] and the
microsomal recovery [mg protein/g liver]:
CL_UP_INT [ml/min/kg]=0.001*CL_INTRINSIC*liver weight*microsomal
recovery [0529] with microsomal recovery=45 mg protein/g liver
[0530] with liver weight=25.7 g liver/kg body weight
[0531] The percent hepatic blood flow (% Q.sub.h) is finally
calculated by considering the human liver blood flow Q
[ml/min/kg]:
% Q.sub.h [%]=((Q*CL_UP_INT)/(Q+CL_UP_INT)/Q)*100 [0532] with liver
blood flow (Q)=20.7 ml/min/kg.
TABLE-US-00021 [0532] TABLE 1 SYK- AURB- FLT3- inhibition
inhibition inhibition IC.sub.50- IC.sub.50- IC.sub.50- Example
value value value No. Structure [.mu.M] [.mu.M] [.mu.M] 6
##STR00066## 0.1508 >50 35.80 34 ##STR00067## 0.0122 >50 7.93
84 ##STR00068## 0.6366 >50 >50
6. COMPARISON OF SYK-INHIBITORY CAPACITY AND OF SYK-SELECTIVITY OF
THE COMPOUNDS OF THE INVENTION COMPARED TO SELECTED COMPOUNDS OF WO
2013/014060 AND OF WO 2011/092128
[0533] To have an efficient SYK-inhibitory capacity is not the only
important aspect which a SYK-inhibitor to be used as a medicament
to treat SYK-related diseases must show. Similarly important like
the low IC.sub.50-value with regard to SYK-inhibition (IV.sub.50
(SYK).ltoreq.1 .mu.M) is that the candidate compound does not show
undesired inhibitory effects on other kinases which could lead to
unwanted or even dangerous side effects. Examples of such other
kinases that should not be inhibited by the candidate SYK-inhibitor
are AURB, FLT3 and GSKbeta.
[0534] Consequently the IC.sub.50-values with regard to SYK, AURB,
FLT3 and GSKbeta for structurally close compounds disclosed in WO
2013/014060 and of WO 2011/092128 have been experimentally
determined according to the same assays as described in chapter 5.
The measured IC.sub.50-values with regard to SYK, AURB, FLT3 and
GSKbeta of these structurally closest prior art compounds are in
the following tables 2a to 6c compared to the respective previously
determined IC.sub.50-values of a representative selection of
compounds of the invention (same assay conditions).
[0535] Further it is desirable for an SYK-inhibitor that is
sufficiently SYK-specific as described above to have certain human
liver microsomal stability (corresponding to CI<60% Q.sub.h;
Q.sub.h=liver blood flow). Otherwise it will be difficult to reach
an adequate plasma level of the SYK-inhibitor in the patient to be
treated. Consequently also the CI-values for structurally close
compounds disclosed in WO 2013/014060 and in WO 2011/092128 have
been experimentally determined according to the same human liver
microsomal-test as described in chapter 5. An experimentally
determined CI-value of more than 60% Q.sub.h is regarded to be
inacceptable in order to reach an adequate plasma level of the
respective SYK-inhibitor in the patient to be treated.
[0536] 6.1 Comparisons with Structurally Similar Prior Art
Compounds
[0537] Whereas all compounds of the invention (see Table 2a), of WO
2013/014060 (see Table 2b) and of WO 2011/092128 (see Table 2c)
have suitable IC.sub.50 (SYK)-values of smaller than 1 .mu.M, only
the compounds of the invention (see Table 2a) have IC.sub.50-values
with regard to AURB of more than 50 .mu.M (compared to
IC.sub.50-values (AURB) of below 3 .mu.M for the compounds of WO
2013/014060 in Table 2b and for the compounds of W02011/092128 in
Table 2c). Also the IC.sub.50-values with respect to FLT3 are
larger for the compounds of the invention (Table 2a) compared to
the compounds of WO 2013/014060 (see Table 2b) and to the compounds
of WO2011/092128 (see Table 2c). Consequently the compounds of the
invention are not only efficient SYK-inhibitors (like the compounds
of WO 2013/014060 (see Table 2b) and of WO2011/092128 (see Table
2c)), but also do not have unwanted inhibitory effects on other
kinases such as AURB, FLT3 and GSK3beta (unlike the compounds of WO
2013/014060 (see Table 2b) and of WO2011/092128 (see Table 2c)).
The compounds of the invention therefore show a significantly
improved SYK-selectivity compared to the structurally closest
compounds disclosed in WO2013/014060 and in WO2011/092128.
TABLE-US-00022 TABLE 2a compounds of the invention GSK3- SYK- AURB-
FLT3- beta inhibition inhibition inhibition inhib. micosomal
IC.sub.50- IC.sub.50- IC.sub.50- IC50- stability Ex. value value
value value Cl No. Structure [.mu.M] [.mu.M] [.mu.M] [.mu.M] [%
Q.sub.h] 6 ##STR00069## 0.1508 >50 35.80 >10 <23 34
##STR00070## 0.0122 >50 7.93 >10 <23 84 ##STR00071##
0.6366 >50 >50 >10 <23
TABLE-US-00023 TABLE 2b Compounds of WO 2013/014060; IC.sub.50
IC.sub.50 IC.sub.50 IC.sub.50 microsomal in .mu.M in .mu.M in .mu.M
in .mu.M stability Ex. (SYK- (AURB- (FLT3- (GSK3beta- Cl No.
Structure Inhibition) Inhibition) Inhibition) Inhibition) [%
Q.sub.h] 112 ##STR00072## 0.006 2.96 1.25 >10 <23 114
##STR00073## 0.0002 2.54 0.049 >10 26 115 ##STR00074## 0.0002
0.021 0.041 >10 <23
TABLE-US-00024 TABLE 2c: Compounds of WO 2011/092128: IC.sub.50
IC.sub.50 IC.sub.50 IC.sub.50 microsomal in .mu.M in .mu.M in .mu.M
in .mu.M stability Ex. (SYK- (AURB- (FLT3- (GSK3beta- Cl No.
Structure Inhibition) Inhibition) Inhibition) Inhibition) [%
Q.sub.h] 3 ##STR00075## 0.0122 1.04 1.82 >10 24 45 ##STR00076##
0.0002 0.086 0.100 >10 53
6. INDICATIONS
[0538] As has been found, the compounds of formula 1 are
characterised by their range of applications in the therapeutic
field. Particular mention should be made of those applications for
which the compounds of formula 1 according to the invention are
preferably used on the basis of their pharmaceutical activity as
Syk-inhibitors. Examples include respiratory complaints, allergic
diseases, osteoporosis, gastrointestinal diseases or complaints,
immune or autoimmune diseases, allergic diseases, inflammatory
diseases, e.g. inflammatory diseases of the joints, skin and eyes
and diseases of the peripheral or central nervous system.
[0539] Particular mention should be made of the prevention and
treatment of respiratory tract and pulmonary diseases which are
accompanied by increased mucus production, inflammation and/or
obstructive diseases of the airways. Examples of these include
asthma, paediatric asthma, ARDS (Adult Respiratory Distress
Syndrome), acute, allergic or chronic bronchitis, autoimmune
haemolytic anemia, chronic obstructive bronchitis (COPD) (including
the treatment of Rhinovirus-induced exacerbations), coughs,
allergic rhinitis or sinusitis, allergic rhinoconjunctivitis,
chronic rhinitis or sinusitis, alveolitis, farmers' lung,
hyperreactive airways, infectious bronchitis or pneumonitis,
bronchiectasis, pulmonary arterial hypertension, pulmonary
fibrosis, bronchial oedema, pulmonary oedema, pneumonia or
interstitial pneumonia triggered by various causes such as
aspiration, inhalation of toxic gases or bronchitis, pneumonia or
interstitial pneumonia triggered by cardiac insufficiency,
radiation, chemotherapy, cystic fibrosis or mucoviscidosis, alpha
1-antitrypsin deficiency.
[0540] The compounds according to the invention are preferably also
suitable for the treatment of allergic diseases such as for example
allergic rhinitis, allergic rhinoconjunctivitis, allergic
conjunctivitis, and contact dermatitis, urticaria/angiooedema and
allergic dermatitis.
[0541] Mention should also preferably be made of the treatment of
inflammatory diseases of the gastrointestinal tract. Examples of
these are Crohn's disease and ulcerative colitis.
[0542] The compounds according to the invention are preferably also
suitable for the treatment of inflammatory diseases of the joints,
of the blood vessels and of the kidney or inflammatory diseases of
the skin and eyes. Examples of these are rheumatoid arthritis,
antibody-based glomerulonephritis, psoriasis, Kawasaki syndrome,
coeliac disease (sprue), arteriosclerosis and Wegener's
granulomatosis, osteoarthritis, systemic scleroderma, ankylosing
spondylitis.
[0543] The compounds according to the invention are preferably also
suitable for the treatment of autoimmune diseases. Examples of
these are hepatitis (autoimmune-based), lupus erythematodes, lupus
nephritis, systemic lupus, Systemic lupus erythematosus,discoid
lupus, cutaneous lupus erythematosus (acute, subacute, chronic),
anti-phospholipid syndrome, Berger's disease, Evans's syndrome,
immunohaemolytic anaemia, ITP (idiopathic thrombocytopenic purpura;
adult, neonatal and paediatric), myasthenia gravis, Sjogren's
syndrome, sclerodermy, Bullous pemphigoid and Pemphigus
vulgaris.
[0544] The compounds according to the invention are preferably also
suitable for the treatment of B-cell lymphomas, like chronic
lymphocytic leukaemia and non-Hodgkin's lymphomas or T cell
lymphomas.
[0545] The compounds according to the invention are preferably also
suitable for the treatment of Graft-versus-host disease.
[0546] Mention may preferably also be made of the prevention and
treatment of diseases of the peripheral or central nervous system.
Examples of these are acute and chronic multiple sclerosis or
non-familial lateral sclerosis.
[0547] Mention may preferably also be made of the prevention and
treatment of osteoporotic diseases such as for example
disease-associated osteopenia, osteoporosis and osteolytic
diseases.
[0548] The present invention relates particularly preferably to the
use of compounds of formula 1 for preparing a pharmaceutical
composition for the treatment of diseases selected from among
asthma, COPD, allergic rhinitis, Adult Respiratory Distress
Syndrome, bronchitis, allergic dermatitis, contact dermatitis, ITP,
rheumatoid arthritis, systemic lupus erythematosus, lupus
nephritis, and allergic rhinoconjunctivitis.
[0549] Most preferably, the compounds of formula 1 may be used for
the treatment of a disease selected from among asthma, allergic
rhinitis, rheumatoid arthritis, systemic lupus erythematosus, lupus
nephritis, allergic dermatitis and COPD.
7. COMBINATIONS
[0550] The compounds of formula 1 may be used on their own or in
conjunction with other active substances of formula 1 according to
the invention. The compounds of formula 1 may optionally also be
used in conjunction with other pharmacologically active substances.
Preferably the active substances used here may be selected for
example from among the betamimetics, anticholinergics,
corticosteroids, PDE4-inhibitors, LTD4-antagonists,
EGFR-inhibitors, MRP4-inhibitors, dopamine agonists,
H1-antihistamines, PAF-antagonists, iNos-inhibitos, HMG-CoA
reductase inhibitors (statins), PI3-kinase-inhibitors,
CCR3-antagonists, CCR2-antagonists, CCR1-antagonists,
IKK2-inhibitors, A2a agonists, alpha-4-integrin-inhibitors,
CRTH2-antagonists, histamine 1, combined H1/H3-antagonists, p38
kinase inhibitors, methylxanthines, ENaC-inhibitors,
CXCR1-antagonists, CXCR2-antagonists, ICE-inhibitors,
LTB4-antagonists, 5-LO antagonists, FLAP-antagonists.
LTB4-antagonists; cromoglycine, dissociated glucocorticoid
mimetics, immunesuppressive agents, cytostatica, non-steroidal
anti-inflammatory drugs (NSAIDs), chloroquine, hydroxychloroquine,
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-IL6 antibodies, anti-IL6 receptor
antibodies, anti-IL-13-antibodies, anti-IL_18 antibodies, anti-CD30
L antibodies, anti-Ox40L-antibodies, anti-IL-4/IL-13-antibodies,
anti-IL-23 (p19) antibodies, anti-IL-12/IL-23 (p40) antibodies,
anti-CD3 antibodies, anti-CD4 antibodies, anti-CD154 antibodies,
CD89 antibodies, anti-IL-2 receptor/CD25 antibodies, anti-CD22
antibodies, anti-interferon antibodies, anti-ICOS antibodies,
anti-ICOS antibodies, anti-CD20 antibodies, anti-CD40 antibodies,
anti-BAFF/BLyS antibodies, anti-CD18 antibodies, anti-CD62L
antibodies, anti-CD147 antibodies, anti-integrin antibodies, agents
interfering with LFA-1, IL-36 pathway modulators, M-CSF/c-fms
antagonists, CTLA-4 fusions, mTor modulators, Toll like receptors 7
inhibitors (TLR7 inhibitor), Toll like receptor 9 inhibitors (TLR9
inhibitors), T cell-costimulatory modulators such as CTLA-4
fusions, JAK inhibitors, IRF modulators, CX3 chemokine receptor
antagonists (CX3CR1 antagonists), IRAK inhibitors (in particular
IRAK1- and IRAK4-inhibitors), Sphingosine-1-phosphate modulators
(S1P pathway modulators),
[0551] or double or triple combinations thereof, such as for
example combinations of one, two or three compounds selected from
among the [0552] Syk-inhibitors of formula 1, betamimetics,
corticosteroids, EGFR-inhibitors and PDE4-antagonists, [0553]
Syk-inhibitors of formula 1, anticholinergics, betamimetics,
corticosteroids, EGFR-inhibitors and PDE4-antagonists, [0554]
Syk-inhibitors of formula 1, PDE4-inhibitors, corticosteroids and
EGFR-inhibitors, [0555] Syk-inhibitors of formula 1,
EGFR-inhibitors and PDE4-inhibitors, [0556] Syk-inhibitors of
formula 1 and EGFR-inhibitors, [0557] Syk-inhibitors of formula 1,
betamimetics and anticholinergics [0558] Syk-inhibitors of formula
1, anticholinergics, betamimetics, corticosteroids and
PDE4-inhibitors, [0559] Syk-inhibitors of formula 1,
anticholinergics, betamimetics, corticosteroids, iNOS inhibitors,
HMG-CoA reductase inhibitors.
[0560] Combinations of three active substances each taken from one
of the above-mentioned categories of compounds are also an object
of the invention.
[0561] Suitable betamimetics used are preferably compounds selected
from among arformoterol, carmoterol, formoterol, indacaterol, sal
meterol, albuterole, bambuterol, bitolterol, broxaterol,
carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol,
isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin,
metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol,
reproterol, rimiterol, ritodrin, salmefamol, soterenol,
sulphonterol, terbutalin, tiaramide, tolubuterol, zinterol,
6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-eth-
ylamino]-ethyl}-4H-benzo[1,4]oxazine-3-one;
8-{2-[2-(2,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6--
hydroxy-4H-benzo[1,4]oxazine-3-one;
8-{2-[2-(3,5-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6--
hydroxy-4H-benzo[1,4]oxazine-3-one;
8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo [1,4]oxazine-3-one;
8-{2-[2-(4-Fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazine-3-one;
N-(5-{2-[3-(4,4-Diethyl-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1-dimethyl--
propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenylymethansulfonamide;
N-(5-{2-[3-(4,4-Diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1--
dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenylymethansulfonamide;
N-(5-{2-[3-(4,4-Diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1-
-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamid-
e;
N-(5-{2-[1,1-Dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazine-1-y-
l)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;
8-{2-[1,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]--
1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;
8-{2-[1,1-Dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-yl)-pro-
pylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;
8-{2-[1,1-Dimethyl-3-(2-oxo-5-trifluormethyl-2,3-dihydro-benzoimidazol-1--
yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;
8-{2-[1,1-Dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-prop-
ylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;
N-[2-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-ph-
enyl]-ethylamino}-ethyly)-phenyl]-formamide;
8-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl-
]-ethylamino}-ethyl)-1H-quinoline-2-one;
8-Hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-qui-
noline-2-one;
5-[(1R)-2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethyla-
mino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one;
[3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-
-hexyloxy}-butyl)-5-methyl-phenyl]-urea;
4-((1R)-2-{6-[2-(2,6-Dichlor-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-eth-
yl)-2-hydroxymethyl-phenol;
3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]--
hexyloxy}-butyl)-benzenesulfonamide;
3-(3-{7-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]--
heptyloxy}-propyl)-benzenesulfonamide;
4-((1R)-2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylaminoyl}-1-h-
ydroxy-ethyl)-2-hydroxymethyl-phenol,
4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)--
2-hydroxymethyl-phenol; Vilanterol;
N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymeth-
yl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
2-(3-{2-[2-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-propyl}-phe-
nyl)-N-[4-(4-hydroxy-phenyl)-2-vinyl-penta-2,4-dienyl]-acetamide;
(1R)-5-{2-[6-(2,2-Difluor-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-
-hydroxy-1H-quinoline-2-one;
(R,S)-4-(2-{[6-(2,2-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)--
2-(hydroxymethyl)phenol;
(R,S)-4-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-hydroxy-ethyl)-2--
(hydroxymethyl)phenol;
(R,S)-4-(2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)--
2-(hydroxymethyl)phenol;
(R,S)-4-(2-{[6-(4,4-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)--
2-(hydroxymethyl)phenol;
(R,S)-5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)--
8-hydroxyquinoline-2(1H)-one;
(R,S)-[2-({6-[2,2-Difluor-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxy-
ethyl]-2-(hydroxymethyl)phenol;
4-(1R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(-
hydroxymethyl)phenol;
(R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5I5-tetrafluor-6-(3-phenylpr-
opoxy)-hexyl]amino}ethyl)phenol;
(R,S)-[5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-hydroxyphenyl]formamide;
(R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydro-
xyethyl]-2-(hydroxymethyl)phenol;
(R,S)--N-[3-(1,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-
phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea;
3-[3-(1,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)
phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione;
(R,S)-4-[2-({6-[2,2-Difluor-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydr-
oxyethyl]-2-(hydroxymethyl)phenol;
5-((1R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8--
hydroxyquinoline-2(1H)-one;
4-((1R)-2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-
-(hydroxymethyl)phenol;
(R,S)-4-(2-{[6-(3,3-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxymethyl)phenol;
(R,S)-(2-{[6-(2,2-Difluor-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydr-
oxyethyl)-2-(hydroxymethyl)phenol;
(R,S)-4-(2-{[6-(2,2-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxy
ethyl)-2-(hydroxymethyl)phenol;
3-[2-(3-Chlor-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-
-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethylypropionamide;
N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazo-
l-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;
7-[2-(2-{3-[2-(2-Chlor-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1--
hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one, optionally in the
form of the racemates, enantiomers, diastereomers and optionally in
the form of the pharmacologically acceptable acid addition salts,
solvates or hydrates thereof.
[0562] According to the invention the acid addition salts of the
betamimetics are preferably selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate,
preferably the hydrochloride, hydrobromide, hydrosulphate,
hydrophosphate, hydrofumarate and hydromethanesulphonate. Of the
above-mentioned acid addition salts the salts of hydrochloric acid,
methanesulphonic acid, benzoic acid and acetic acid are
particularly preferred according to the invention.
[0563] The anticholinergics used are preferably compounds selected
from among tiotropium salts, particularly the bromide salt,
oxitropium salts, particularly the bromide salt, flutropium salts,
particularly the bromide salt, ipratropium salts, particularly the
bromide salt, Aclidinium salts, particularly the bromide salt,
glycopyrronium salts, particularly the bromide salt, trospium
salts, particularly the chloride salt, tolterodin,
(3R)-1-Phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octa-
n-salts; 2,2-Diphenyl propionic acid tropenole ester-methobromide;
2,2-Diphenyl propionic acid scopine ester-methobromide;
2-Fluor-2,2-Diphenyl acetic acid scopine ester-methobromide;
2-Fluor-2,2-Diphenyl acetic acid tropenole ester-methobromide;
3,3',4,4'-Tetrafluor benzilic acid tropenole ester-methobromide;
3,3',4,4'-Tetrafluor benzilic acid scopine ester-methobromide;
4,4'-Difluor benzilic acid tropenole ester-methobromide;
4,4'-Difluor benzilic acid scopine ester-methobromide; 3,3'-Difluor
benzilic acid tropenole ester-methobromide; 3,3'-Difluor benzilic
acid scopine ester-methobromide; 9-Hydroxy-fluorene-9-carboxylic
acid tropenole ester-methobromide; 9-Fluor-fluorene-9-carboxylic
acid tropenole ester-methobromide; 9-Hydroxy-fluorene-9-carboxylic
acid scopine ester-methobromide; 9-Fluor-fluorene-9-carboxylic acid
scopine ester-methobromide; 9-Methyl-fluorene-9-carboxylic acid
tropenole ester-methobromide; 9-Methyl-fluorene-9-carboxylic acid
scopine ester-methobromide; Benzilic acid cyclopropyl tropine
ester-methobromide; 2,2-Diphenyl propionic acid cyclopropyltropine
ester-methobromide; 9-Hydroxy-xanthene-9-carboxylic acid
cyclopropyltropine ester-methobromide;
9-Methyl-fluorene-9-carboxylic acid cyclopropyltropine
ester-methobromide; 9-Methyl-xanthene-9-carboxylic acid
cyclopropyltropine ester-methobromide;
9-Hydroxy-fluorene-9-carboxilic acid cyclopropyltropine
ester-methobromide; 4,4'-Difluor benzilic acid methyl ester
cyclopropyltropine ester-methobromide;
9-Hydroxy-xanthene-9-carboxylic acid tropenole ester-methobromide;
9-Hydroxy-xanthene-9-carboxylic acid scopine ester-methobromide;
9-Methyl-xanthene-9-carboxylic acid tropenole ester-methobromide;
9-Methyl-xanthene-9-carboxylic acid scopine ester-methobromide;
9-Ethyl-xanthene-9-carboxylic acid tropenole ester-methobromide;
9-Difluormethyl-xanthene-9-carboxylic acid tropenole
ester-methobromide; 9-Hydroxymethyl-xanthene-9-carboxylic acid
scopine ester-methobromide;
[0564]
3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4--
hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionami-
de;
[0565]
N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzo-
thiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide-
;
[0566]
7-[2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylam-
ino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one and
Darotropium;
[0567] optionally in the form of the solvates or hydrates
thereof.
[0568] In the above-mentioned salts the cations tiotropium,
oxitropium, flutropium, ipratropium, glycopyrronium, aclidinium and
trospium are the pharmacologically active ingredients. As anions,
the above-mentioned salts may preferably contain chloride, bromide,
iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,
acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate
or p-toluenesulphonate, while chloride, bromide, iodide, sulphate,
methanesulphonate or p-toluenesulphonate are preferred as
counter-ions. Of all the salts, the chlorides, bromides, iodides
and methanesulphonate are particularly preferred.
[0569] Of particular importance is tiotropium bromide. In the case
of tiotropium bromide the pharmaceutical combinations according to
the invention preferably contain it in the form of the crystalline
tiotropium bromide monohydrate, which is known from WO 02/30928. If
the tiotropium bromide is used in anhydrous form in the
pharmaceutical combinations according to the invention, it is
preferable to use anhydrous crystalline tiotropium bromide, which
is known from WO 03/000265.
[0570] Corticosteroids used here are preferably compounds selected
from among beclomethasone, betamethasone, budesonide, butixocort,
ciclesonide, deflazacort, dexamethasone, etiprednole, flunisolide,
fluticasone, loteprednole, mometasone, prednisolone, prednisone,
rofleponide, triamcinolone, tipredane; Pregna-1,4-diene-3,20-dione,
6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)
bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-,
(6-alpha,11-beta,16-alpha)-(9Cl);
16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-
-3-one;
6,9-Difluor-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-
-androsta-1,4-dien-17-carbothione acid (S)-fluoromethylester;
(S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate;
6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,-
2,3,3-tetramethylcyclopropylcarbonyl)oxy-and
rosta-1,4-diene-17beta-carboxylic acid cyanomethyl ester, each
optionally in the form of the racemates, enantiomers or
diastereomers thereof and optionally in the form of the salts and
derivatives, solvates and/or hydrates thereof.
[0571] Particularly preferably the steroid is selected from among
budesonide, fluticasone, mometasone, ciclesonide and
(S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate, optionally in the form of the
racemates, enantiomers or diastereomers thereof and optionally in
the form of the salts and derivatives, solvates and/or hydrates
thereof.
[0572] Any reference to steroids includes a reference to any salts
or derivatives, hydrates or solvates thereof which may exist.
Examples of possible salts and derivatives of the steroids may be:
alkali metal salts, such as for example sodium or potassium salts,
sulfobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates or furoates
thereof.
[0573] PDE4 inhibitors which may be used are preferably compounds
selected from among enprofyllin, theophyllin, roflumilast, ariflo
(cilomilast), tofimilast, pumafentrin, lirimilast, apremilast,
arofyllin, atizoram, oglemilast, tetomilast;
5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-Quinoline
(D-4418);
5-[N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy--
2-(trifluoromethyl)-Quinoline (D-4396 (Sch-351591));
N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyox-
ylic acid amide (AWD-12-281 (GW-842470));
9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-Purin-6-amine
(NCS-613);
4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-Pyridine
(CDP-840);
N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]b-
enzodiazepin-3-yl]-4-Pyridinecarboxamide (PD-168787);
4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-
-2(1H)-Pyridinone (T-440);
2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4--
(3-pyridinyl)-1(2H)-Phthalazinone (T-2585);
(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine
(V-11294A);
beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-lsoind-
ole-2-propanamide (CDC-801);
Imidazo[1,5-a]pyrido[3,2-e]pyrazine-6(5H)-one,
9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888);
5-[3-(cyclopentyloxy)-4-methoxypheny]-3-[(3-methylphenyl)methyl]-,
(3S,5S)-2-Piperidinon (HT-0712);
4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)eth-
yl]-alpha,alpha-bis(trifluoromethyl)-Benzenemethanol (L-826141);
N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluormethoxy-3-cyclopropylmethoxy-
benzamide;
(-)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy--
2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide;
(R)-(+)-1-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrroli-
don;
3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothi-
oureido]benzyl)-2-pyrrolidon;
cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic
acid];
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyph-
enyl)cyclohexan-1-one;
cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan-1-o-
l];
(R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]-
acetat;
(S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yli-
den]acetat;
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo[4,3-a]pyridin;
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridin,
[0574] optionally in the form of the racemates, enantiomers or
diastereomers and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates and/or hydrates
thereof.
[0575] By acid addition salts with pharmacologically acceptable
acids which the above-mentioned PDE4-inhibitors might be in a
position to form are meant, for example, salts selected from among
the hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,
hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
[0576] LTD4-antagonists which may be used are preferably compounds
selected from among montelukast, pranlukast, zafirlukast;
(E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl-
)-4H-1-benzopyran-4-one (MEN-91507);
4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propyl-
phenoxy]-butyric acid (MN-001);
1-(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-
-propyl)phenyl)thio)methylcyclopropane-acetic acid;
1-(((1(R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)pheny-
l)-3-(2-(1-hydroxy-1-methylethyl)phenyl)
propyl)thio)methyl)cyclopropane acetic acid;
[2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]
acetic acid,
[0577] optionally in the form of the racemates, enantiomers or
diastereomers, optionally in the form of the pharmacologically
acceptable acid addition salts and optionally in the form of the
salts and derivatives, solvates and/or hydrates thereof.
[0578] By acid addition salts with pharmacologically acceptable
acids which the LTD4-antagonists may be capable of forming are
meant, for example, salts selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate. By salts or derivatives which the
LTD4-antagonists may be capable of forming are meant, for example:
alkali metal salts, such as, for example, sodium or potassium
salts, alkaline earth metal salts, sulphobenzoates, phosphates,
isonicotinates, acetates, propionates, dihydrogen phosphates,
palmitates, pivalates or furoates.
[0579] The EGFR-inhibitors used are preferably compounds selected
from among
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2--
butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
e-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
ne-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl-
]amino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine--
4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine--
4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazo-
line,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-
-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazol-
ine,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholi-
ne-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
ne-1-yl]amino}-7-cyclopentyloxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4N-(2-methoxy-ethyl)-N-ethyl-amino]-1-o-
xo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
ne-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
ne-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-butene-1-yl}amino)-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-
-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
ne-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
ne-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(-
vinylcarbonyl)amino]-quinazoline,
4-[(R)-(1-phenyl-ethypamino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimi-
dine,
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-
-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline,
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulpho-
nyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)--
1-oxo-2-butene-1-yl]amino}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-
-1-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino-
]-1-oxo-2-butene-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-
,
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholine-4-yl)-1-
-oxo-2-butene-1-yl]amino}-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-
-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-
-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2.2-dimethyl-6-oxo-morpholine-4-
-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piper-
idine-1-yl]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperid-
ine-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-met-
hoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-pipe-
ridine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
dine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-quin-
azoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-pi-
peridine-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hyd-
roxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonyl-
amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulphony-
lamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidine-1-yl)carbonyl]-pipe-
ridine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidine-4-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbony-
l]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazolin;
4-{2-[4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-eth-
yl}-6-methyl-morpholine-2-one,
4-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyc-
lohexyl}-1-methyl-piperazine-2-one,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)sulphon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cycloh-
exan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yl-
oxy)-7-ethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yl-
oxy)-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4--
yloxy]-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidine-4-yl-
oxy]-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidine-1-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1-y-
l)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholine-4-yl)carbonylam-
ino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-pipe-
ridine-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidine-4-yloxy)-7-methoxy-qui-
nazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-me-
thoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yloxy)-7-m-
ethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7(2-m-
ethoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidine--
4-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(piperidine-4-yloxy)-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-
-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-
-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholine-4--
yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholine-4-yl)carbo-
nyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,-
1]hept-5-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amin-
o)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidine-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbony-
l]-piperidine-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carbo-
nyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-
-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yl-
oxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-meth-
oxy-quinazoline,
3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo--
2-butene-1-yl]amino}-7-ethoxy-quinoline,
[4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholine-4-yl)-1-oxo-2--
butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-
-yl)carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazolin-
e,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine-
-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholine-4-
-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholine-4-
-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-
-yl)carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazolin-
e,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine-
-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholine-4-
-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholine-4-
-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, cetuximab,
trastuzumab, panitumumab(=ABX-EGF), Mab ICR-62, gefitinib,
pelitinib, canertinib and erlotinib, optionally in the form of the
racemates, enantiomers or diastereomers thereof, optionally in the
form of the pharmacologically acceptable acid addition salts
thereof, the solvates and/or hydrates thereof.
[0580] By acid addition salts with pharmacologically acceptable
acids which the EGFR-inhibitors may be capable of forming are
meant, for example, salts selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
[0581] Examples of dopamine agonists which may be used preferably
include compounds selected from among bromocriptine, cabergoline,
alpha-dihydroergocryptine, lisuride, pergolide, pramipexol,
roxindol, ropinirol, talipexol, terguride and viozan. Any reference
to the above-mentioned dopamine agonists within the scope of the
present invention includes a reference to any pharmacologically
acceptable acid addition salts and optionally hydrates thereof
which may exist. By the physiologically acceptable acid addition
salts which may be formed by the above-mentioned dopamine agonists
are meant, for example, pharmaceutically acceptable salts which are
selected from the salts of hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methanesulphonic acid, acetic
acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid and maleic acid.
[0582] Examples of H1-antihistamines preferably include compounds
selected from among epinastine, cetirizine, azelastine,
fexofenadine, levocabastine, loratadine, mizolastine, ketotifen,
emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine,
pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate,
diphenhydramine, promethazine, ebastine, olopatadine, desloratidine
and meclozine. Any reference to the above-mentioned
H1-antihistamines within the scope of the present invention
includes a reference to any pharmacologically acceptable acid
addition salts which may exist.
[0583] Examples of PAF-antagonists preferably include compounds
selected from among lexipafant,
4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thien-
o-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,
6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpho-linyl)carbonyl]-4H,7-
H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.
Any reference to the above-mentioned above-mentioned
PAF-antagonists includes within the scope of the present invention
a reference to any pharmacologically acceptable acid addition salts
thereof which may exist.
[0584] Examples of non-steroidal anti-inflammatory drugs (NSAIDs)
preferably include compounds selected from among Aceclofenac,
Acemetacin, Acetylsalicylsaure, Alclofenac, Alminoprofen, Amfenac,
Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenin, Azapropazon,
Benorilat, Bermoprofen, Bindarit, Bromfenac, Bucloxinsaure,
Bucolom, Bufexamac, Bumadizon, Butibufen, Butixirat,
Carbasalatcalcium, Carprofen, Cholin Magnesium Trisalicylat,
Celecoxib, Cinmetacin, Cinnoxicam, Clidanac, Clobuzarit, Deboxamet,
Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam,
Eltenac, Enfenaminsaure, Etersalat, Etodolac, Etofenamat,
Etoricoxib, Feclobuzon, Felbinac, Fenbufen, Fenclofenac,
Fenoprofen, Fentiazac, Fepradinol, Feprazon, Flobufen, Floctafenin,
Flufenaminsaure, Flufenisal, Flunoxaprofen, Flurbiprofen,
Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, Ibufenac,
Ibuprofen, Indobufen, Indometacin, Indometacinfarnesil, Indoprofen,
Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac,
Lornoxicam, Loxoprofen, Lumiracoxib, Meclofenaminsaure, Meclofen,
Mefenaminsaure, Meloxicam, Mesalazin, Miroprofen, Mofezolac,
Nabumeton, Naproxen, Nifluminsaure, Olsalazin, Oxaprozin, Oxipinac,
Oxyphenbutazon, Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen,
Pirazolac, Priroxicam, Pirprofen, Pranoprofen, Prifelon, Prinomod,
Proglumetacin, Proquazon, Protizininsaure, Rofecoxib, Romazarit,
Salicylamid, Salicylsaure, Salmistein, Salnacedin, Salsalat,
Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenidap, Tenosal,
Tenoxicam, Tepoxalin, Tiaprofensaure, Taramid, Tilnoprofenarbamel,
Timegadin, Tinoridin, Tiopinac, Tolfenaminsaure, Tolmetin,
Ufenamat, Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen.
[0585] MRP4-inhibitors used are preferably compounds selected from
among N-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,
dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone
3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol
17-beta-glucuronide, estradiol 3,17-disulphate, estradiol
3-glucuronide, estradiol 3-sulphate, estrone 3-sulphate,
flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate,
glycolithocholic acid sulphate, ibuprofen, indomethacin,
indoprofen, ketoprofen, lithocholic acid sulphate,
methotrexate,((E)-3-[[[3-[2-(7-chloro-2-q uinol
inyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-pro-
panoic acid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl
mercaptopurine riboside, probenecid, sildenafil, sulfinpyrazone,
taurochenodeoxycholate, taurocholate, taurodeoxycholate,
taurolithocholate, taurolithocholic acid sulphate, topotecan,
trequinsin and zaprinast, dipyridamole, optionally in the form of
the racemates, enantiomers, diastereomers and the pharmacologically
acceptable acid addition salts and hydrates thereof.
[0586] Examples of JAK inhibitors preferably include compounds
selected from among Tofacitinib and Ruxolitinib.
[0587] Examples of immunesuppressive agents preferably include
compounds selected from among mycophenolate mofetil, mycophenolic
acid, azathioprine, cyclosporine, tacrolimus, pimecrolimus,
abetimus, gusperimus and leflunomide.
[0588] An example of a cytostaticum is cyclophosphamide.
[0589] The invention relates more preferably to the use of
MRP4-inhibitors for preparing a pharmaceutical composition for
treating respiratory complaints, containing the Syk-inhibitors of
formula 1 and MRP4-inhibitors according to the invention, the
MRP4-inhibitors preferably being selected from among
dehydroepiandrosterone 3-sulphate, estradiol 3,17-disulphate,
flurbiprofen, indomethacin, indoprofen, taurocholate, optionally in
the form of the racemates, enantiomers, diastereomers and the
pharmacologically acceptable acid addition salts and hydrates
thereof. The separation of enantiomers from the racemates can be
carried out using methods known from the art (e.g. chromatography
on chiral phases, etc.).
[0590] By acid addition salts with pharmacologically acceptable
acids are meant, for example, salts selected from among the
hydrochlorides, hydrobromides, hydroiodides, hydrosulphates,
hydrophosphates, hydromethanesulphonates, hydronitrates,
hydromaleates, hydroacetates, hydrobenzoates, hydronitrates,
hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates,
hydrobenzoates and hydro-p-toluenesulphonates, preferably the
hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates,
hydrofumarates and hydromethanesulphonates.
[0591] The invention further relates to pharmaceutical preparations
which contain a triple combination of the Syk-inhibitors of formula
1, MRP4-inhibitors and another active substance according to the
invention, such as, for example, an anticholinergic, a PDE4
inhibitor, a steroid, an LTD4-antagonist or a betamimetic, and the
preparation thereof and the use thereof for treating respiratory
complaints.
[0592] Compounds which may be used as iNOS inhibitors are compounds
selected from among: S-(2-aminoethyl)isothiourea, aminoguanidine,
2-aminomethylpyridine,
5,6-dihydro-6-methyl-4H-1,3-Thiazine-2-amine(=AMT), L-canavanine,
2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea,
S-ethylisothiourea, S-methyltiocitrullin, S-ethylthiocitrulline,
L-NA (N.sup..omega.-nitro-L-arginine), L-NAME
(N.sup..omega.-nitro-L-argininemethylester), L-NMMA
(N.sup.G-monomethyl-L-arginine), L-NIO
(N.sup..omega.-iminoethyl-L-ornithine), L-NIL
(N.sup..omega.-iminoethyl-lysine),
(S)-6-acetimidoylamino-2-amino-hexanoic acid
(1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45,
1686-1689),
N-[[3-(aminomethyl)phenyl]methyl]-Ethanimidamide(=1400W),
(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid
(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),
2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine
(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),
2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO
01/62704),
2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluorome-
thyl-nicotinonitrile (WO 2004/041794),
2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benz-
onitrile (WO 2004/041794),
2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benz-
onitrile (WO 2004/041794),
(2S.4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol--
5-yl-butan-1-ol (WO 2004/041794),
2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nico-
tinonitrile (WO 2004/041794),
4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitri-
le (WO 02/090332), substituted
3-phenyl-3,4-dihydro-1-isoquinolinamine such as e.g.
(1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine
(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),
(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med.
Chem. 2004, 12, 4101),
(4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine (Bioorg. Med.
Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine (Curr.
Drug Metabol. 2002, 3, 119-121),
(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-y-
loxy)-piperidine-1-yl]ethylcarbamoyl}-2-pyridin-2-yl-ethylyacrylamide
(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),
3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-ph-
enyl-pyridine (PPA250) (J. Pharmaco Exp. Ther. 2002, 303, 52-57),
3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-p-
yrimidin-4-yl)-piperazine-1-carboxylate (BBS-1) (Drugs Future 2004,
29, 45-52),
(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-car-
boxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)amide (BBS-2) (Drugs
Future 2004, 29, 45-52) and the pharmaceutical salts, prodrugs or
solvates thereof.
[0593] Examples of iNOS-inhibitors within the scope of the present
invention may also include antisense oligonucleotides, particularly
those antisense oligonucleotides which bind iNOS-coding nucleic
acids. For example, WO 01/52902 describes antisense
oligonucleotides, particularly antisense oligonucleotides, which
bind iNOS coding nucleic acids, for modulating the expression of
iNOS. iNOS-antisense oligonucleotides as described particularly in
WO 01/52902 may therefore also be combined with the PDE4-inhibitors
of the present invention on account of their similar effect to the
iNOS-inhibitors.
[0594] Suitable HMG-CoA reductase inhibitors (also called statins)
which may be preferably used in double or triple combinations with
the compounds of formula 1 are selected from among Atorvastatin,
Cerivastatin, Flurvastatin, Lovastatin, Pitavastatin, Pravastatin,
Rosuvastatin, Simvastatin, optionally in form of their
pharmaceutically available acid addition salts, prodrugs, solvates
or hydrates thereof.
8. FORMULATIONS
[0595] Suitable forms for administration are for example tablets,
capsules, solutions, syrups, emulsions or inhalable powders or
aerosols. The content of the pharmaceutically effective compound(s)
in each case should be in the range from 0.1 to 90 wt. %,
preferably 0.5 to 50 wt. % of the total composition, i.e. in
amounts which are sufficient to achieve the dosage range specified
hereinafter.
[0596] The preparations may be administered orally in the form of a
tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine
capsule), as a solution or suspension. When administered by
inhalation the active substance combination may be given as a
powder, as an aqueous or aqueous-ethanolic solution or using a
propellant gas formulation.
[0597] Preferably, therefore, pharmaceutical formulations are
characterised by the content of one or more compounds of formula 1
according to the preferred embodiments above.
[0598] It is particularly preferable if the compounds of formula 1
are administered orally, and it is also particularly preferable if
they are administered once or twice a day. Suitable tablets may be
obtained, for example, by mixing the active substance(s) with known
excipients, for example inert diluents such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as corn starch or
alginic acid, binders such as starch or gelatine, lubricants such
as magnesium stearate or talc and/or agents for delaying release,
such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several
layers.
[0599] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0600] Syrups containing the active substances or combinations
thereof according to the invention may additionally contain a
sweetener such as saccharine, cyclamate, glycerol or sugar and a
flavour enhancer, e.g. a flavouring such as vanillin or orange
extract. They may also contain suspension adjuvants or thickeners
such as sodium carboxymethyl cellulose, wetting agents such as, for
example, condensation products of fatty alcohols with ethylene
oxide, or preservatives such as p-hydroxybenzoates.
[0601] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules. Suitable
suppositories may be made for example by mixing with carriers
provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0602] Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g. petroleum fractions), vegetable oils (e.g. groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or
glycerol), carriers such as e.g. natural mineral powders (e.g.
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane
sugar, lactose and glucose), emulsifiers (e.g. lignin, spent
sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone)
and lubricants (e.g. magnesium stearate, talc, stearic acid and
sodium lauryl sulphate).
[0603] For oral administration the tablets may, of course, contain,
apart from the abovementioned carriers, additives such as sodium
citrate, calcium carbonate and dicalcium phosphate together with
various additives such as starch, preferably potato starch,
gelatine and the like. Moreover, lubricants such as magnesium
stearate, sodium lauryl sulphate and talc may be used at the same
time for the tabletting process. In the case of aqueous suspensions
the active substances may be combined with various flavour
enhancers or colourings in addition to the excipients mentioned
above.
[0604] It is also preferred if the compounds of formula 1 are
administered by inhalation, particularly preferably if they are
administered once or twice a day. For this purpose, the compounds
of formula 1 have to be made available in forms suitable for
inhalation. Inhalable preparations include inhalable powders,
propellant-containing metered-dose aerosols or propellant-free
inhalable solutions, which are optionally present in admixture with
conventional physiologically acceptable excipients.
[0605] Within the scope of the present invention, the term
propellant-free inhalable solutions also includes concentrates or
sterile ready-to-use inhalable solutions. The preparations which
may be used according to the invention are described in more detail
in the next part of the specification.
[0606] Inhalable Powders
[0607] If the active substances of formula 1 are present in
admixture with physiologically acceptable excipients, the following
physiologically acceptable excipients may be used to prepare the
inhalable powders according to the invention: monosaccharides (e.g.
glucose or arabinose), disaccharides (e.g. lactose, saccharose,
maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols
(e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients with one
another. Preferably, mono- or disaccharides are used, while the use
of lactose or glucose is preferred, particularly, but not
exclusively, in the form of their hydrates. For the purposes of the
invention, lactose is the particularly preferred excipient, while
lactose monohydrate is most particularly preferred. Methods of
preparing the inhalable powders according to the invention by
grinding and micronising and by finally mixing the components
together are known from the prior art.
[0608] Propellant-Containing Inhalable Aerosols
[0609] The propellant-containing inhalable aerosols which may be
used according to the invention may contain the compounds of
formula 1 dissolved in the propellant gas or in dispersed form. The
propellant gases which may be used to prepare the inhalation
aerosols according to the invention are known from the prior art.
Suitable propellant gases are selected from among hydrocarbons such
as n-propane, n-butane or isobutane and halohydrocarbons such as
preferably fluorinated derivatives of methane, ethane, propane,
butane, cyclopropane or cyclobutane. The propellant gases mentioned
above may be used on their own or in mixtures thereof. Particularly
preferred propellant gases are fluorinated alkane derivatives
selected from TG134a (1,1,1,2-tetrafluoroethane), TG227
(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The
propellant-driven inhalation aerosols used within the scope of the
use according to the invention may also contain other ingredients
such as co-solvents, stabilisers, surfactants, antioxidants,
lubricants and pH adjusters. All these ingredients are known in the
art.
[0610] Propellant-Free Inhalable Solutions
[0611] The compounds of formula 1 according to the invention are
preferably used to prepare propellant-free inhalable solutions and
inhalable suspensions. Solvents used for this purpose include
aqueous or alcoholic, preferably ethanolic solutions. The solvent
may be water on its own or a mixture of water and ethanol. The
solutions or suspensions are adjusted to a pH of 2 to 7, preferably
2 to 5, using suitable acids. The pH may be adjusted using acids
selected from inorganic or organic acids. Examples of particularly
suitable inorganic acids include hydrochloric acid, hydrobromic
acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples
of particularly suitable organic acids include ascorbic acid,
citric acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid and/or propionic acid etc.
Preferred inorganic acids are hydrochloric and sulphuric acids. It
is also possible to use the acids which have already formed an acid
addition salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid and citric acid are preferred.
If desired, mixtures of the above acids may also be used,
particularly in the case of acids which have other properties in
addition to their acidifying qualities, e.g. as flavourings,
antioxidants or complexing agents, such as citric acid or ascorbic
acid, for example. According to the invention, it is particularly
preferred to use hydrochloric acid to adjust the pH.
[0612] Co-solvents and/or other excipients may be added to the
propellant-free inhalable solutions used for the purpose according
to the invention. Preferred co-solvents are those which contain
hydroxyl groups or other polar groups, e.g. alcohols--particularly
isopropyl alcohol, glycols--particularly propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The
terms excipients and additives in this context denote any
pharmacologically acceptable substance which is not an active
substance but which can be formulated with the active substance or
substances in the pharmacologically suitable solvent in order to
improve the qualitative properties of the active substance
formulation. Preferably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents,
antioxidants and/or preservatives which guarantee or prolong the
shelf life of the finished pharmaceutical formulation, flavourings,
vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium
chloride as isotonic agents. The preferred excipients include
antioxidants such as ascorbic acid, for example, provided that it
has not already been used to adjust the pH, vitamin A, vitamin E,
tocopherols and similar vitamins or provitamins occurring in the
human body. Preservatives may be used to protect the formulation
from contamination with pathogens. Suitable preservatives are those
which are known in the art, particularly cetyl pyridinium chloride,
benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art.
[0613] For the treatment forms described above, ready-to-use packs
of a medicament for the treatment of respiratory complaints are
provided, containing an enclosed description including for example
the words respiratory disease, COPD or asthma, together with a
imidazolyl-pyrimidine according to formula 1 and one or more
combination partners selected from those described above.
* * * * *