U.S. patent application number 12/232973 was filed with the patent office on 2009-02-05 for imidazopyridine-derivatives as inductible no-synthase inhibitors.
This patent application is currently assigned to Altana Pharma AG. Invention is credited to Wolf-Ruediger Ulrich.
Application Number | 20090036482 12/232973 |
Document ID | / |
Family ID | 34384571 |
Filed Date | 2009-02-05 |
United States Patent
Application |
20090036482 |
Kind Code |
A1 |
Ulrich; Wolf-Ruediger |
February 5, 2009 |
Imidazopyridine-derivatives as inductible no-synthase
inhibitors
Abstract
The compounds of Formula (I) ##STR00001## in which R1, R2, R3,
R4, R5 and A have the meanings as given in the description are
novel effective iNOS inhibitors.
Inventors: |
Ulrich; Wolf-Ruediger;
(Konstanz, DE) |
Correspondence
Address: |
NATH & ASSOCIATES PLLC
112 South West Street
Alexandria
VA
22314
US
|
Assignee: |
Altana Pharma AG
Konstanz
DE
|
Family ID: |
34384571 |
Appl. No.: |
12/232973 |
Filed: |
September 26, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10573484 |
Mar 24, 2006 |
7468377 |
|
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PCT/EP04/52378 |
Sep 30, 2004 |
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12232973 |
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Current U.S.
Class: |
514/303 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 31/00 20180101; A61P 25/02 20180101; A61P 25/28 20180101; A61P
27/02 20180101; A61P 9/00 20180101; A61K 31/437 20130101; A61P 1/04
20180101; A61P 9/10 20180101; A61P 25/06 20180101; A61P 11/08
20180101; A61P 25/16 20180101; A61P 11/06 20180101; A61P 29/00
20180101; A61P 17/06 20180101; A61P 17/00 20180101; A61P 25/00
20180101; A61P 43/00 20180101; C07D 471/04 20130101; A61P 3/10
20180101 |
Class at
Publication: |
514/303 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 29/00 20060101 A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 1, 2003 |
EP |
03022053.7 |
Claims
1.-14. (canceled)
15. A method for treating an acute inflammatory disease in a
patient comprising administering to said patient a therapeutically
effective amount of a compound of formula I ##STR00009## in which
R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is
hydrogen or halogen, R4 is hydrogen, halogen, 1-4C-alkyl or
1-4C-alkoxy, R5 is 1-4C-alkyl, A is 1-4C-alkylene, or a salt,
N-oxide or a salt of an N-oxide thereof.
16. The method of claim 15, wherein said compound has one of the
formulae Ia, Ib or Ic: ##STR00010## or a salt, N-oxide or a salt of
an N-oxide thereof.
17. The method of claim 15, wherein said compound has one of the
formulae I, Ia, Ib or Ic in which R1 is hydrogen or 1-4C-alkyl, R2
is hydrogen or 1-4C-alkyl, R3 is hydrogen or halogen, R4 is
hydrogen, R5 is methyl, A is ethylene, or a salt, N-oxide or a salt
of an N-oxide thereof.
18. The method of claim 15, wherein said compound has one of the
formulae I, Ia, Ib or Ic in which R1 is hydrogen, methyl or ethyl,
R2 is hydrogen, methyl or ethyl, R3 is hydrogen or fluorine, R4 is
hydrogen, R5 is methyl, A is ethylene, or a salt, N-oxide or a salt
of an N-oxide thereof.
19. The method of claim 15, wherein said compound has one of the
formulae I, Ia, Ib or Ic in which either R1 is methyl, R2 is
methyl, and R3 is fluorine, or R1 is hydrogen, methyl or ethyl, R2
is hydrogen, methyl or ethyl, and R3 is hydrogen, R4 is hydrogen,
R5 is methyl, A is ethylene, or a salt, N-oxide or a salt of an
N-oxide thereof.
20. The method of claim 15, wherein said compound has one of the
formulae Ib or Ic in which R1 is hydrogen, methyl or ethyl, R2 is
hydrogen, methyl or ethyl, R3 is hydrogen or fluorine, R4 is
hydrogen, R5 is methyl, A is ethylene, or a salt, N-oxide or a salt
of an N-oxide thereof.
21. The method of claim 15, wherein said compound has the formula
Ic in which either R1 is methyl, R2 is methyl, and R3 is fluorine,
or R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or
ethyl, and R3 is hydrogen, R4 is hydrogen, R5 is methyl, A is
ethylene, or a salt, N-oxide or a salt of an N-oxide thereof.
22. The method of claim 15, wherein said compound has the formula
Id TABLE-US-00003 (Id) ##STR00011## in which R1, R2 and R3 have any
one of the following meanings 1 to 12: R1 R2 R3 1. H H H 2. H
CH.sub.3 H 3. H CH.sub.2CH.sub.3 H 4. H H F 5. H CH.sub.3 F 6. H
CH.sub.2CH.sub.3 F 7. CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H 8.
CH.sub.3 CH.sub.3 H 9. CH.sub.3 CH.sub.2CH.sub.3 H 10.
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 F 11. CH.sub.3 CH.sub.3 F 12.
CH.sub.3 CH.sub.2CH.sub.3 F
or a salt, N-oxide or a salt of an N-oxide thereof.
23. A method for treating a chronic inflammatory disease of
peripheral organs and the central nervous system (CNS) in a patient
comprising administering to said patient a therapeutically
effective amount of a compound of formula I ##STR00012## in which
R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is
hydrogen or halogen, R4 is hydrogen, halogen, 1-4C-alkyl or
1-4C-alkoxy, R5 is 1-4C-alkyl, A is 1-4C-alkylene, or a salt,
N-oxide or a salt of an N-oxide thereof.
24. The method of claim 23, wherein said compound has one of the
formulae Ia, Ib or Ic: ##STR00013## or a salt, N-oxide or a salt of
an N-oxide thereof.
25. The method of claim 23, wherein said compound has one of the
formulae I, Ia, Ib or Ic in which R1 is hydrogen or 1-4C-alkyl, R2
is hydrogen or 1-4C-alkyl, R3 is hydrogen or halogen, R4 is
hydrogen, R5 is methyl, A is ethylene, or a salt, N-oxide or a salt
of an N-oxide thereof.
26. The method of claim 23, wherein said compound has one of the
formulae I, Ia, Ib or Ic in which R1 is hydrogen, methyl or ethyl,
R2 is hydrogen; methyl or ethyl, R3 is hydrogen or fluorine, R4 is
hydrogen, R5 is methyl, A is ethylene, or a salt, N-oxide or a salt
of an N-oxide thereof.
27. The method of claim 23, wherein said compound has one of the
formulae I, Ia, Ib or Ic in which either R1 is methyl, R2 is
methyl, and R3 is fluorine, or R1 is hydrogen, methyl or ethyl, R2
is hydrogen, methyl or ethyl, and R3 is hydrogen, R4 is hydrogen,
R5 is methyl, A is ethylene, or a salt, N-oxide or a salt of an
N-oxide thereof.
28. The method of claim 23, wherein said compound has one of the
formulae Ib or Ic in which R1 is hydrogen, methyl or ethyl, R2 is
hydrogen, methyl or ethyl, R3 is hydrogen or fluorine, R4 is
hydrogen, R5 is methyl, A is ethylene, or a salt, N-oxide or a salt
of an N-oxide thereof.
29. The method of claim 23, wherein said compound has the formula
Ic in which either R1 is methyl, R2 is methyl, and R3 is fluorine,
or R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or
ethyl, and R3 is hydrogen, R4 is hydrogen, R5 is methyl, A is
ethylene, or a salt, N-oxide or a salt of an N-oxide thereof.
30. The method of claim 23, wherein said compound has the formula
Id TABLE-US-00004 (Id) ##STR00014## in which R1, R2 and R3 have any
one of the following meanings 1 to 12: R1 R2 R3 1. H H H 2. H
CH.sub.3 H 3. H CH.sub.2CH.sub.3 H 4. H H F 5. H CH.sub.3 F 6. H
CH.sub.2CH.sub.3 F 7. CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H 8.
CH.sub.3 CH.sub.3 H 9. CH.sub.3 CH.sub.2CH.sub.3 H 10.
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 F 11. CH.sub.3 CH.sub.3 F 12.
CH.sub.3 CH.sub.2CH.sub.3 F
or a salt, N-oxide or a salt of an N-oxide thereof.
Description
FIELD OF APPLICATION OF THE INVENTION
[0001] The invention relates to novel imidazopyridine derivatives,
which are used in the pharmaceutical industry for the production of
pharmaceutical compositions.
KNOWN TECHNICAL BACKGROUND
[0002] In the German Patent Application DE 2504252 and in the
European Patent Application EP 0125756 3H-imidazo[4,5-b]pyridine
derivatives with anti-ulcer activity are described. The
international Application WO 0049015 describes pyridine compounds
with inhibitory activity on the production of nitric oxide.
[0003] The international Application WO 0380607 describes
alkoxypyridine derivatives with iNOS Inhibitory activity.
DESCRIPTION OF THE INVENTION
[0004] It has now been found that certain novel, purposively
selected aminosulfonylphenyl-substituted Imidazopyridine
derivatives, which are described in greater details below, differ
profoundly from previously individualized compounds and have
surprising and particularly advantageous and desired
properties.
[0005] The invention thus relates to compounds of formula I
##STR00002##
in which
[0006] R1 is hydrogen or 1-4C-alkyl,
[0007] R2 is hydrogen or 1-4C-alkyl,
[0008] R3 is hydrogen or halogen,
[0009] R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
[0010] R5 is 1-4C-alkyl,
[0011] A is 1-4C-alkylene, and the salts, N-oxides and the salts of
the N-oxides of these compounds.
[0012] 1-4-C-Alkyl is a straight-chain or branched alkyl radical
having 1 to 4 carbon atoms. Examples are the butyl, isobutyl,
sec-butyl, tert-butyl, propyl, isopropyl, and, particularly, the
ethyl and methyl radicals.
[0013] 1-4C-Alkoxy is a radical which, in addition to the oxygen
atom, contains a straight-chain or branched alkyl radical having 1
to 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms which
may be mentioned in this context are, for example, the butoxy,
isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, and,
particularly, the ethoxy and methoxy radicals.
[0014] 1-4C-Alkylene is a straight chain alkylene radical having 1
to 4 carbon atoms. Examples which may be mentioned in this context
are the methylene (--CH.sub.2--), ethylene
(--CH.sub.2--CH.sub.2--), trimethylene
(--CH.sub.2--CH.sub.2--CH.sub.2--) and the tetramethylene
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) radical.
[0015] Halogen stands for chlorine or fluorine.
[0016] N-oxide denotes the N-oxide on the pyridine which is
substituted by the --O--R5 radical.
[0017] Suitable salts for compounds according to the
invention--depending on substitution--are all acid addition salts
or all salts with bases. Particular mention may be made of the
pharmacologically tolerable inorganic and organic adds and bases
customarily used in pharmacy. Those suitable are, on the one hand,
water-insoluble and, particularly, water-soluble acid addition
salts with adds such as, for example, hydrochloric acid,
hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid,
acetic acid, citric add, D-gluconic add, benzoic add,
2-(4-hydroxybenzoyl)benzoic acid, butyric add, sulphosalicylic
acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic
acid, oxalic add, tartaric acid, embonic acid, stearic acid,
toluenesulphonic acid, methanesulphonic acid or
3-hydroxy-2-naphthoic add, the acids being employed in salt
preparation--depending on whether a mono- or polybasic acid is
concerned and depending on which salt is desired--in an equimolar
quantitative ratio or one differing therefrom.
[0018] On the other hand, salts with bases are--depending on
substitution--also suitable. As examples of salts with bases are
mentioned the lithium, sodium, potassium, calcium, aluminium,
magnesium, titanium, ammonium, meglumine or guanidinium salts,
here, too, the bases being employed in salt preparation in an
equimolar quantitative ratio or one differing therefrom.
[0019] Pharmacologically intolerable salts, which can be obtained,
for example, as process products during the preparation of the
compounds according to the invention on an industrial scale, are
converted into pharmacologically tolerable salts by processes known
to the person skilled in the art.
[0020] According to experts knowledge the compounds of the
invention as well as their salts may contain, e.g. when isolated in
crystalline form, varying amounts of solvents. Included within the
scope of the invention are therefore all solvates and in particular
all hydrates of the compounds according to this invention as well
as all solvates and in particular all hydrates of the salts of the
compounds according to this invention.
[0021] A person skilled in the art knows on the base of his/her
expert knowledge that the compounds according to this invention can
exist, with regard to the fused imidazo ring of the imidazopyridine
system, in different tautomeric forms such as e.g. in the 1-H form
or, preferably, in the 3-H form, which is shown in formula I. The
invention includes all conceivable tautomers in pure form as well
as in any mixing ratio. Particularly the present invention includes
the pure 1-H-- and, preferably, 3-H-tautomers as well as any
mixtures thereof.
[0022] An embodiment of the compounds of the present invention
include those compounds of formula I in which R5 is methyl.
[0023] Another embodiment of the compounds of the present invention
include those compounds of formula I in which A is ethylene.
[0024] Another embodiment of the compounds of the present invention
include those compounds of formula I in which R4 is hydrogen.
[0025] Another embodiment of the compounds of the present invention
include those compounds of formula I in which R5 is methyl and A is
ethylene.
[0026] Another embodiment of the compounds of the present invention
include those compounds of formula I in which R4 is hydrogen, R5 is
methyl and A is ethylene.
[0027] Another embodiment of the compounds of the present invention
include those compounds of formula I in which the aminosulphonyl
substituted phenyl moiety is bonded to the 6-position of the
imidazopyridine ring.
[0028] The substituent R3 and the aminosulphonyl radical of
compounds according to this invention can be attached in the ortho,
meta or para position with respect to the binding position in which
the phenyl ring is bonded to the imidazopyridine ring system,
whereby in an embodiment of the present invention the
aminosulphonyl radical is attached in the para position.
[0029] In this context, another embodiment of the compounds of the
present invention include those compounds of formula I in which R3
is attached in the meta position and the aminosulphonyl radical is
attached in the para position with respect to the binding position
in which the phenyl ring is bonded to the imidazopyridine ring
system.
[0030] Another special embodiment of the compounds of the present
invention include those compounds which have one of the formulae
Ia, Ib or Ic as shown below.
[0031] Compounds according to this invention worthy to be mentioned
are those compounds of formula I, in which
R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is
hydrogen or halogen, R4 is hydrogen, R5 is methyl, A is ethylene,
and the salts, N-oxides and the salts of the N-oxides of these
compounds.
[0032] Compounds according to this invention more worthy to be
mentioned are those compounds of formula I, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen, chlorine or fluorine, R4 is hydrogen, R5 is methyl,
A is ethylene, and the salts, N-oxides and the salts of the
N-oxides of these compounds.
[0033] Compounds according to this invention in particular worthy
to be mentioned are those compounds of formula I, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen or fluorine, R4 is hydrogen, R5 is methyl, A is
ethylene, and the salts, N-oxides and the salts of the N-oxides of
these compounds.
[0034] Compounds according to this invention in more particular
worthy to be mentioned are those compounds of formula I, in which
either
R1 is methyl, R2 is methyl, and R3 is fluorine, or R1 is hydrogen,
methyl or ethyl, R2 is hydrogen, methyl or ethyl, and R3 is
hydrogen, R4 is hydrogen, R5 is methyl, A is ethylene, and the
salts, N-oxides and the salts of the N-oxides of these
compounds.
[0035] An embodiment (embodiment a) worthy to be mentioned of this
invention include compounds of formula Ia
##STR00003##
in which R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or
1-4C-alkyl, R3 is hydrogen or halogen, R4 is hydrogen,
R5 is 1-4C-alkyl,
A is 1-4C-alkylene,
[0036] and the salts, N-oxides and the salts of the N-oxides of
these compounds.
[0037] Compounds according to embodiment a worthy to be mentioned
are those compounds of formula Ia, in which
R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is
hydrogen or halogen, R4 is hydrogen, R5 is methyl, A is ethylene,
and the salts, N-oxides and the salts of the N-oxides of these
compounds.
[0038] Compounds according to embodiment a more worthy to be
mentioned are those compounds of formula Ia, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen, chlorine or fluorine, R4 is hydrogen, R5 is methyl,
A is ethylene, and the salts, N-oxides and the salts of the
N-oxides of these compounds.
[0039] Compounds according to embodiment a in particular worthy to
be mentioned are those compounds of formula Ia, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen or fluorine, R4 is hydrogen, R5 is methyl, A is
ethylene, and the salts, N-oxides and the salts of the N-oxides of
these compounds.
[0040] Compounds according to embodiment a in more particular
worthy to be mentioned are those compounds of formula Ia, in which
either
R1 is methyl, R2 is methyl, and R3 is fluorine, or R1 is hydrogen,
methyl or ethyl, R2 is hydrogen, methyl or ethyl, and R3 is
hydrogen, R4 is hydrogen, R5 is methyl, A is ethylene, and the
salts, N-oxides and the sails of the N-oxides of these
compounds.
[0041] A preferred embodiment (embodiment b) of this invention
include compounds of formula Ib
##STR00004##
in which R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or
1-4C-alkyl, R3 is hydrogen or halogen, R4 is hydrogen, R5 is
methyl, A is ethylene, and the salts, N-oxides and the salts of the
N-oxides of these compounds.
[0042] Compounds according to embodiment b more worthy to be
mentioned are those compounds of formula Ib, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen, chlorine or fluorine, R4 is hydrogen, R5 is methyl,
A is ethylene, and the salts, N-oxides and the salts of the
N-oxides of these compounds.
[0043] Compounds according to embodiment b in particular worthy to
be mentioned are those compounds of formula Ib, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen or fluorine, R4 is hydrogen, R5 is methyl, A is
ethylene, and the salts, N-oxides and the salts of the N-oxides of
these compounds.
[0044] Compounds according to embodiment b in more particular
worthy to be mentioned are those compounds of formula Ib, in which
either
R1 is methyl, R2 is methyl, and R3 is fluorine, or R1 is hydrogen,
methyl or ethyl, R2 is hydrogen, methyl or ethyl, and R3 is
hydrogen, R4 is hydrogen, R5 is methyl, A is ethylene, and the
salts, N-oxides and the salts of the N-oxides of these
compounds.
[0045] A more preferred embodiment (embodiment c) of this invention
include compounds of formula Ic
##STR00005##
in which R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen or
1-4C-alkyl, R3 is hydrogen or halogen, R4 is hydrogen, R5 is
methyl, A is ethylene, and the salts, N-oxides and the salts of the
N-oxides of these compounds.
[0046] Compounds according to embodiment c more worthy to be
mentioned are those compounds of formula Ic, in which
R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl,
R3 is hydrogen, chlorine or fluorine, R4 is hydrogen, R5 is methyl,
A is ethylene, and the salts, N-oxides and the salts of the
N-oxides of these compounds.
[0047] Compounds according to embodiment c in particular worthy to
be mentioned are those compounds of formula Ic, in which
either R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or
ethyl, R3 is hydrogen or fluorine, R4 is hydrogen, R5 is methyl, A
is ethylene, and the salts, N-oxides and the salts of the N-oxides
of these compounds.
[0048] Compounds according to embodiment c in more particular
worthy to be mentioned are those compounds of formula Ic, in
which
either R1 is methyl, R2 is methyl, and R3 is fluorine, or R1 is
hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl, and R3
is hydrogen, R4 is hydrogen, R5 is methyl, A is ethylene, and the
salts, N-oxides and the salts of the N-oxides of these
compounds.
[0049] As exemplary compounds according to this invention the
following compounds of formula Id
##STR00006##
are to be mentioned by means of the substituent meanings for R1, R2
and R3 in the following Table 1.
TABLE-US-00001 TABLE 1 R1 R2 R3 H H H H CH.sub.3 H H
CH.sub.2CH.sub.3 H H H F H CH.sub.3 F H CH.sub.2CH.sub.3 F
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H CH.sub.3 CH.sub.3 H CH.sub.3
CH.sub.2CH.sub.3 H CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 F CH.sub.3
CH.sub.3 F CH.sub.3 CH.sub.2CH.sub.3 F and the salts, N-oxides and
the salts of the N-oxides of these compounds.
[0050] Compounds according to this invention can be obtained as
described below and shown in the following reaction schemes, or as
specified by way of example in the following examples or similarly
or analogously thereto.
[0051] Thus, as shown in reaction scheme 1 below, a compound of
formula II, in which R4, R5 and A have the meanings given above and
X is a suitable leaving group, preferably bromine or, particularly,
iodine, is reacted with boronic acids or, particularly, boronic
acid esters (e.g. pinacol esters) of formula IIa, in which R1, R2
and R3 have the meanings given above and Y is a boronic acid group
or, particularly, a boronic acid ester group, suitably a cyclic
boronic add ester group such as, for example, the boronic acid
pinacol ester group, under conditions appropriate for a Suzuki
reaction to occur to give compounds of formula I, in which R1, R2,
R3, R4, R5 and A have the meanings mentioned above.
##STR00007##
[0052] Suitably, the Suzuki reaction is carried out as it is known
to the person of ordinary skill in the art and/or in a manner as it
is described below and specified by way of example in the following
examples or analogously or similarly thereto.
[0053] In more detail, the Suzuki reaction mentioned can be carried
out in organic solvents alone, for example in toluene, benzene,
dimethylformamide or in ethereal (e.g. dimethoxyethane or, in
particular, dioxane) or alcohol solvents or in a mixture thereof,
or preferably in a mixture comprising an organic solvent (in
particular dioxane) and water, with organic (e.g. triethylamine) or
preferably inorganic base (e.g. potassium hydroxide, thallium
hydroxide, sodium bicarbonate, cesium carbonate, cesium fluoride
or, in particular, potassium carbonate) in the presence of a
transition metal catalyst, for example, a nickel or, in particular,
palladium catalyst (e.g. Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2
or, In particular, Pd(PPh.sub.3).sub.4), and, optionally, lithium
chloride. The reaction is carried out at a temperature in the range
from 20.degree. to 160.degree. C., usually 60.degree. to
130.degree. C. for 10 minutes to 5 days, usually 30 minutes to 24
hours. Advantageously, the solvents used are degassed and the
reaction is carried out under protective gas.
[0054] The Suzuki reaction is for example described in Tetrahedron
Lett. 1998, 39, 4467, J. Org. Chem. 1999, 64, 1372 or Heterocycles
1992, 34, 1395. A general review of Suzuki cross-couplings between
boronic acids and aryl halides can be found in Miyaura, N; Suzuki,
A. Chem. Rev. 1995, 95, 2457.
[0055] Boronic acids or boronic add esters (e.g. pinacol esters) of
formula IIa, in which R1, R2, R3 and Y have the meanings given
above, are known or can be obtained in an art-known manner or
analogously or similarly to known compounds. Boronic acid esters
(e.g. pinacol esters) of formula IIa can be prepared, for example,
as described in the following examples starting from phenyl
triflates or, particularly, phenyl halides, preferably the bromides
or iodides, using e.g. bis(pinacolato)-diboron in the presence of a
transition metal, preferably palladium, catalyst. Optionally the
boronic acid esters obtained can be isolated or, preferably, they
are generated in situ and used in the subsequent Suzuki reaction
without isolation.
[0056] Compounds of formula II, in which R4, R5, X and A have the
meanings given above, are obtained as exemplarily described in the
following examples or shown in the following reaction scheme 2 or
similarly or analogously thereto.
[0057] In the following reaction scheme 2 the synthesis of
compounds of formula II, in which R4. R5 and X have the meanings
given above and A is ethylene, is exemplarily described.
[0058] The carbon chain in 2-position of the compounds of formula
VII is lengthened, for example, by a condensation (with a malonic
acid derivative) and a subsequent hydrogenation reaction.
Alternatively, the carbon chain can be lengthened using a Wittig
reaction followed by a hydrogenation reaction.
[0059] The methyl 3-(4-(1-4C)alkoxypyridin-2-yl)propionate
(compound of formula V) or the corresponding acid (compound of
formula IV), which can be obtained in an art-known manner, are
converted with a 2,3-diaminopyridine derivative (compound of
formula III) to give the desired compounds of formula II.
##STR00008##
[0060] The synthesis of 4-methoxy-pyridin-2-carbaldehyde (compound
of formula VII) is described for example in Ashimori et al, Chem
Pharm Bull 38, 2446-2458 (1990).
[0061] Compounds of formula VII can be also prepared starling from
commercially available 4-nitro-2-picoline-N-oxide by exchange of
the nitro group by an 1-C-alkoxy group. The resulting 4-(1-4C)
alkoxy-2-picoline-N-oxide is then via a rearrangement and an
oxidation step converted to 4-(1-4C) alkoxy-pyridin-2-carbaldehyd
(compound of formula VII).
[0062] The synthesis of 3-(4-methoxypyridin-2-yl)propionic acid
(compound of formula IV) is described in the paragraph Starting
Materials.
[0063] Compounds of formula II, in which R4 and X have the meanings
indicated above, are known or can be prepared in a known manner or
analogously or similarly to art-known compounds.
[0064] Optionally, the compounds according to this invention can be
converted into their salts, or, optionally, salts of the compounds
according to this invention can be converted into the free
compounds. Corresponding processes are known to the person skilled
in the art.
[0065] The compounds according to this invention can be converted,
optionally, into their N-oxides, for example with the aid of
hydrogen peroxide in methanol or with the aid of
m-chloroperoxybenzoic acid in dichloromethane. The person skilled
in the art is familiar on the basis of his/her expert knowledge
with the reaction conditions which are specifically necessary for
carrying out the N-oxidation.
[0066] It is known to the person skilled in the art that if there
are a number of reactive centers on a starting or intermediate
compound it may be necessary to block one or more reactive centers
temporarily by protective groups in order to allow a reaction to
proceed specifically at the desired reaction center. A detailed
description for the use of a large number of proven protective
groups is found, for example, in T. W. Greene, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1999, 3.sup.rd Ed, or in
P. Kocienski, Protecting Groups, Thieme Medical Publishers,
2000.
[0067] The substances according to the invention are isolated and
purified in a manner known per se, e.g. by distilling off the
solvent in vacuo and recrystallizing the residue obtained from a
suitable solvent or subjecting it to one of the customary
purification methods, such as column chromatography on a suitable
support material.
[0068] Salts are obtained by dissolving the free compound in a
suitable solvent (for example a ketone like acetone,
methylethylketone, or methylisobutylketone, an ether, like diethyl
ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such
as methylene chloride or chloroform, or a low molecular weight
aliphatic alcohol, such as ethanol, isopropanol) which contains the
desired acid, or to which the desired acid is then added. The salts
are obtained by filtering, reprecipitating, precipitating with a
non-solvent for the addition salt or by evaporating the solvent.
Salts obtained can be converted by basification into the free
compounds which, in turn, can be converted into salts. In this
manner, pharmacologically non-tolerable salts can be converted into
pharmacologically tolerable salts.
[0069] Suitably, the conversions mentioned in this invention can be
carried out analogously or similarly to methods which are familiar
per se to the person skilled in the art for example, in the manner
which is described by way of example in the following examples.
[0070] The person skilled in the art knows on the basis of his/her
knowledge and on the basis of those synthesis routes, which are
shown and described within the description of this invention, how
to find other possible synthesis routes for compounds according to
this invention. All these other possible synthesis routes are also
part of this invention.
[0071] Having described the invention in detail, the scope of the
present invention is not limited only to those described
characteristics or embodiments. As will be apparent to persons
skilled in the art, modifications, analogies, variations,
derivations, homologisations and adaptations to the described
invention can be made on the base of art-known knowledge and/or,
particularly, on the base of the disclosure (e.g. the explicite,
implicite or inherent disclosure) of the present invention without
departing from the spirit and scope of this invention as defined by
the scope of the appended claims.
[0072] The following examples illustrate the invention in greater
detail, without restricting it. As well, further compounds
according to the present invention, of which the preparation is
explicitly not described, can be prepared in an analogous way or in
a way which is known by a person skilled in the art using customary
preparation methods and process techniques.
[0073] The compounds, which are mentioned in the examples as well
as their salts are a preferred subject of the invention.
[0074] In the examples, m.p. stands for melting point, h for hours,
d for days, min for minutes, TLC for thin layer chromatography, Rf
for retention factor, MS for mass spectrum, M for molecular ion,
other abbreviations have their meanings customary per se for the
skilled person.
EXAMPLES
Final Products
1.
4-{2-[2-(4-Methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N,-
N-dimethyl-benzenesulfonamide
[0075] A mixture of 1.984 g of
N,N-dimethyl-4-bromobenzenesulfonamide, 2.1 g of
bis-(pinacolato)-diboron, 0.125 g of
1,1'-bis-(diphenylphosphino)ferrocene, 0.165 g of
[1,1'-bis(diphenylphosphino)ferrocene]palladium-dichloride (complex
with CH.sub.2Cl.sub.2), 2.21 g of potassium acetate in 50 ml of
degassed dioxane are heated to reflux under N.sub.2 for 16 hours.
To the resulting mixture 40 ml of degassed dioxane, 2.14 g of
2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine
(starting material A1), 0.65 g of
tetrakis(triphenylphos-phine)palladium(0) and a solution of 1.56 g
of potassium carbonate and 0.48 g of lithium chloride in 40 ml of
degassed water are added under N.sub.2. The mixture is heated to
reflux under N.sub.2 for 7 hours and, after cooling, addition of
water and adjusting the pH to 7, it is extracted three times with
dichloromethane. The combined organic phases are dried over sodium
sulfate, concentrated and the residue is chromatographed on a
silica gel column (dichloromethane/methanol 30-15:1). Concentration
of the chromatographically pure fractions, crystallisation from
methanol and recrystallization from ethylacetate gives 2.01 g of
the title compound as a solid of m.p. 217-218.degree. C. The mass
spectrum shows the molecular peak MH.sup.+ at 438.3 Da.
2. N,N-Diethyl-4-{2-[2-(4
methoxypyridin-2-yl)ethyl]-3H-imidazo-[4,5-b]pyridin-6-yl}benzenesulfonam-
ide
[0076] A mixture of 0.438 g of
N,N-diethyl-4-bromobenzenesulfonamide, 0.42 g of
bis-pinacolato)-diboron, 0.025 g of
1,1'-bis-(diphenylphosphino)-ferrocene, 0.033 g of
[1,1'-bis(diphenylphosphino)ferrocene]palladium-dichloride (complex
with CH.sub.2Cl.sub.2), 0.442 g of potassium acetate in 6 ml of
degassed dioxane are heated to 90.degree. C. In a sealed tube under
N.sub.2 for 7 hours. To the resulting mixture 10 ml of degassed
dioxane, 0.371 g of
2-[2-4-methoxypyridin-2-yl)ethyl]-iodo-3H-imidazo[4,5-b]pyridine
(starting material A1), 0.113 g of
tetrakis(triphenylphos-phine)palladium(0) and a solution of 0.27 g
of potassium carbonate and 0.083 g of lithium chloride in 10 ml of
degassed water are added under N.sub.2. The mixture is heated to
reflux under N.sub.2 for 16 hours and, after cooling, addition of
water and adjusting the pH to 7, it is extracted three times with
dichloromethane. The combined organic phases are dried over sodium
sulfate, concentrated and the residue is chromatographed on a
silica gel column (dichloromethane/methanol 30-25:1). Concentration
of the chromatographically pure fractions and crystallisation from
ethylacetate gives 0.155 g of the title compound as a solid of m.p.
127-129.degree. C. The mass spectrum shows the molecular peak
MH.sup.+ at 466.3 Da.
3.
4-{2-[2-(4-Methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N--
methyl-benzenesulfonamide
[0077] A mixture of 0.375 g of N-methyl-4-bromobenzenesulfonamide,
0.42 g of bis-(pinacolato)-diboron, 0.025 g of
1,1'-bis-(diphenylphosphino)ferrocene, 0.033 g of
[1,1'-bis(diphenylphosphino) ferrocene]palladium-dichloride
(complex with CH.sub.2Cl.sub.2), 0.442 g of potassium acetate in 6
ml of degassed dioxane are heated to 90.degree. C. in a sealed tube
under N.sub.2 for 16 hours. To the resulting mixture 5 ml of
degassed dioxane, 0.371 g of
2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine
(starting material A1), 0.113 g of
tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g
of potassium carbonate and 0.083 g of lithium chloride in 5 ml of
degassed water are added under N.sub.2. The tube is sealed again,
the mixture is heated to 90.degree. under N.sub.2 for 8 hours and,
after cooling, addition of water and adjusting the pH to 7, it is
extracted three times with dichloromethane. The combined organic
phases are dried over sodium sulfate, concentrated and the residue
is chromatographed on a silica gel column (dichloromethane/methanol
20-15:1). Concentration of the chromatographically pure fractions
and crystallisation from ethyacetate gives 0.219 g of the title
compound as a solid of m.p. 225-227.degree. C. The mass spectrum
shows the molecular peak MH.sup.+ at 424.3 Da.
4.
4-{2-[2-(4-Methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-be-
nzenesulfonamide
[0078] A mixture of 0.354 g of 4-bromobenzenesulfonamide, 0.42 g of
bis-(pinacolato)-diboron, 0.025 g of
1,1'-bis-(diphenylphosphino)-ferrocene, 0.033 g of
[1,1'-bis(diphenylphosphino)ferrocene]-palladium-dichloride
(complex with CH.sub.2Cl.sub.2), 0.442 g of potassium acetate in 6
ml of degassed dioxane are heated to 125.degree. C. in a sealed
tube under N.sub.2 for 16 hours. To the resulting mixture 5 ml of
degassed dioxane, 0.371 g of
2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine
(starting material A1), 0.113 g of
tetrakis(triphenylphos-phine)-palladium(0) and a solution of 027 g
of potassium carbonate and 0.083 g of lithium chloride in 5 ml of
degassed water are added under N.sub.2. The tube is sealed again,
the mixture is heated to 115.degree. under N.sub.2 for 7 hours and,
after cooling, addition of water and adjusting the pH to 7, it is
extracted three times with dichloromethane. The combined organic
phases are dried over sodium sulfate, concentrated and the residue
is chromatographed on a silica gel column (dichloromethane/methanol
12:1+1% NH.sub.4OH). Concentration of the chromatographically pure
fractions gives 0.08 g of the title compound as a brownish solid of
m.p. 216-218.degree. C. The mass spectrum shows the molecular peak
MH.sup.+ at 410.2 Da.
5.
N-Ethyl-4-{2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo-[4,5-b]pyridin-
-6-yl}benzenesulfonamide
[0079] A mixture of 0.348 g of N-ethyl-4-bromobenzenesulfonamide,
0.42 g of bis-(pinacolato)-diboron, 0.025 g of
1,1'-bis-(diphenylphosphino)-ferrocene, 0.033 g of
[1,1'-bis(diphenylphosphino)-ferrocene]palladium-dichloride
(complex with CH.sub.2Cl.sub.2), 0.442 g of potassium acetate in 6
ml of degassed dioxane are heated to 90.degree. C. in a sealed-tube
under N.sub.2 for 17 hours. To the resulting mixture 5 ml of
degassed dioxane, 0.371 g of
2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine
(starting material A1), 0.113 g of
tetrakis(triphenylphos-phine)-palladium(0) and a solution of 0.27 g
of potassium carbonate and 0.083 g of lithium chloride in 5 ml of
degassed water are added under N.sub.2. The tube is sealed again,
the mixture is heated to 115.degree. under N.sub.2 for 7 hours and,
after cooling, addition of water and adjusting the pH to 7, it is
extracted three times with dichloromethane. The combined organic
phases are dried over sodium sulfate, concentrated and the residue
is chromatographed on a silica gel column (dichloromethane/methanol
25-15:1). Concentration of the chromatographically pure fractions
and crystallisation from ethylacetate gives 0.248 g of the title
compound as a solid of m.p. 214-216.degree. C. The mass spectrum
shows the molecular peak MH.sup.+ at 438.4 Da.
6.
2-Fluoro-4-{2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-
-6-yl}-N,N-dimethyl-benzenesulfonamide
[0080] A mixture of 0.423 g of
N,N-dimethyl-4-bromo-2-fluorobenzenesulfonamide, 0.42 g of
bis-(pinacolato diboron, 0.025 g of
1,1'-bis-(diphenylphosphino)-ferrocene, 0.033 g of
[1,1'-bis(diphenylphosphino)-ferrocene]palladium-dichloride
(complex with CH.sub.2Cl.sub.2), 0.442 g of potassium acetate in 6
ml of degassed dioxane are heated to 90.degree. C. In a sealed tube
under N.sub.2 for 17 hours. To the resulting mixture 5 ml of
degassed dioxane, 0.371 g of
2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine
(starting material A1), 0.113 g of
tetrakis(triphenylphos-phine)-palladium(0) and a solution of 0.27 g
of potassium carbonate and 0.083 g of lithium chloride in 5 ml of
degassed water are added under N.sub.2. The tube is sealed again,
the mixture is heated to 115.degree. under N.sub.2 for 7 hours and,
after cooling, addition of water and adjusting the pH to 7, it is
extracted three times with dichloromethane. The combined organic
phases are dried over sodium sulfate, concentrated and the residue
is chromatographed on a silica gel column (dichloromethane/methanol
25-22:1). Concentration of the chromatographically pure fractions
and crystallisation from ethylacetate gives 0.27 g of the title
compound as a solid of m.p. 211-212.degree. C. The mass spectrum
shows the molecular peak MH.sup.+ at 456.3 Da.
Starting materials:
A1.
2-[2-(4-Methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine
[0081] With stirring, a mixture of 8.06 g of
3-(4-methoxypyridin-2-yl)propionic acid (starting material B1), 9.5
g of 2,3-diamino-5-iodopyridine (Cugola et al., Bioorg. Med. Chem.
Lett 22, 2749-2754 (1996)) and 150 g of polyphosphoric acid (PPA)
is heated at 140.degree. C. for 22 hours. After cooling, the
mixture is poured into about 1000 ml of ice-water and then
neutralized (pH 7-8) using 6N aqueous sodium hydroxide solution.
The mixture is extracted four times with ethyl acetate and the
combined organic phases are evaporated to dryness. The residue is
crystallized first from ethyl acetate and then from methanol,
giving 9.4 g of the title compound as a light-beige powder of m.p.
207-208.degree. C.; the mass spectrum shows the molecular peak
MH.sup.+ at 381.2 Da.
B1. 3-(4-Methoxypyridin-2-yl)propionic acid
[0082] 41.95 g of methyl 3-(4-methoxypyridin-2-yl)propionate
(starting material C1) are dissolved in 700 ml of tetrahydrofuran,
and 217 ml of 1N sodium hydroxide solution are added. The mixture
is stirred at RT until no more starting material is detectable
(TLC). The mixture is neutralized using 217 ml of 1N hydrochloric
add solution, evaporated to dryness and dried under high vacuum.
The colorless residue is ground and extracted four times with
dichloromethane/methanol (9:1). The combined extracts are
evaporated to dryness. This gives 33.2 g of the title compound as a
colorless powder of m.p. 131-132.degree. C. The mass spectrum shows
the molecular peak MH.sup.+ at 182 Da.
C1. Methyl 3-(4-methoxypyridin-2-yl)propionate
[0083] 43.1 g of methyl 3-(4-methoxypyridin-2-yl)acrylate (starting
material D1) in 600 ml of methanol are hydrogenated over 3.0 g of
Pd/C (10% strength) until the starting material has disappeared
(TLC). The catalyst is filtered off, and the mixture is then
concentrated and dried under high vacuum. This gives 41.95 g of the
title compound as a light-yellow oil. The mass spectrum shows the
molecular peak MH.sup.+ at 196 Da.
D1. Methyl 3-(4-methoxypyridin-2-yl)acrylate
[0084] A mixture of 45 g of 4-methoxypyridine-2-carbaldehyde
(Ashimori et al., Chem. Pharm. Bull. 38, 2446-2458 (1990)), 75.80 g
of pyridine hydrochloride, 102.45 g of monomethyl malonate
potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are
slowly heated, with stirring, to 120.degree. C. When the evolution
of gas starts, the heating source is temporarily removed to stop
the reaction from becoming too violent. Once the reaction has
subsided, the mixture is stirred at 120.degree. C. for a further
2.5 hours, and the pyridine is then distilled off under reduced
pressure. The residue is partitioned between ethyl acetate/water
and the organic phase is washed with water and dried. The residue
obtained after concentration is chromatographed on a silica gel
column using ethyl acetate/petroleum ether 2:1. This initially
gives 432 g of the title compound as a yellow oil which
crystallizes on standing and then shows a m.p. of 80-82.degree. C.
The mass spectrum shows the molecular peak MH.sup.+ at 194 Da.
Commercial Applicability
[0085] The compounds according to the invention have valuable,
desired and emphasis worth pharmacological properties which make
them commercially utilizable. They are selective inhibitors of the
enzyme inducible nitric oxide synthase. Nitric oxide syntheses
(NO-syntases, NOSS) are enzymes that generate NO and citrulline
from the amino acid arginine. In certain pathophysiological
situations such as arginine depletion or tetrahydrobiopterin
depletion the generation of O.sub.2.sup.- from NO-synthases instead
or together with NO has been reported. NO is long known as a
signalling molecule in most living organisms including mammals and
humans. The most prominent action of NO is it's smooth muscle
relaxing activity, which is caused on the molecular level by the
activation of soluble guanylate cyclase. In the last years a lot of
other enzymes have been shown to be regulated by NO or reaction
products of NO.
[0086] There exist three isoforms of NO-synthases which fall into
two classes and differ in their physiologic functions and molecular
properties. The first class, known as constitutive NO-synthases,
comprises of the endothelial NO-synthase and the neuronal
NO-synthase. Both isoenzymes are expressed constitutively in
various cell types, but are most prominent in endothelial cells of
blood vessel walls (therefore called endothelial NO-synthase, eNOS
or NOS-III) and in neuronal cells (therefore called neuronal
NO-synthase, nNOS or NOS-III). Activation of these two enzymes is
dependent on Ca.sup.2+/Calmodulin which is generated by transient
increases of the intracellular free Ca.sup.2+ concentration.
Activation of constitutive isoforms leads to transient bursts of
nitric oxide resulting in nanomolar cellular or tissue NO
concentrations. The endothelial isoform is involved in the
physiologic regulation of blood pressure. NO generated by the
neuronal isoform seems to have neurotransmitter function and the
neuronal isoform is among other regulatory processes involved in
memory function (long term potentiation).
[0087] In contrast to the constitutive isoforms the activation of
inducible NO-synthase (iNOS, NOS-II), the sole member of the second
class, Is performed by transcriptional activation of the
iNOS-promoter. Proinflammatory stimuli lead to transcription of the
gene for inducible NO-synthase, which is catalytically active
without increases in the intracellular Ca.sup.2+-concentration. Due
to the long half live of the inducible NO-synthase and the
unregulated activity of the enzyme, high micromolar concentrations
of NO are generated over longer time periods. These high
NO-concentrations alone or in cooperation with other reactive
radicals such as 0.degree. are cytotoxic. Therefore, in situations
of microbial infections, iNOS is involved in cell killing by
macrophages and other immune cells during early nonspecific immune
responses.
[0088] There are a number of pathophysiological situations which
among others are characterized by the high expression of inducible
NO-synthase and concomitant high NO or O.sub.2.sup.-
concentrations. It has been shown that these high NO concentrations
alone or in combination with other radical species lead to tissue
and organ damage and are causally involved in these
pathophysiologies. As inflammation is characterized by the
expression of proinflammatory enzymes, including inducible
NO-synthase, acute and chronical inflammatory processes are
promising diseases for the therapeutic application of selective
inhibitors of inducible NO-synthase. Other pathophysiologies with
high NO-production from inducible NO-synthase are several forms of
shock (septic, hemorrhagic and cytokine-induced). It is clear that
nonselective NO-synthase inhibitors will lead to cardiovascular and
neuronal side effects due to concomitant inhibition of constitutive
NO-synthase isoforms.
[0089] It has been shown in in-vivo animal models of septic shock
that reduction of circulating plasma NO-levels by NO-scavenger or
inhibition of inducible NO-synthase restores systemic blood
pressure, reduces organ damage and increases survival (deAngelo
Exp. Opin. Pharmacother. 19-29, 1999; Redl et al. Shock 8. Suppl.
51, 1997; Strand et al. Crit. Care Med. 26, 1490-1499, 1998). It
has also been shown that increased NO production during septic
shock contributes to cardiac depression and myocardial dysfunction
(Sun et al. J. Mol. Cell Cardiol. 30, 989-997, 1998). Furthermore
there are also reports showing reduced infarct size after occlusion
of the left anterior coronary artery in the presence of NO-synthase
inhibitors (Wang et al. Am. J. Hyperttens. 12, 174-182, 1999).
Considerable inducible NO-synthase activity is found in human
cardiomyopathy and myocarditis, supporting the hypothesis that NO
accounts at least in part for the dilatation and impaired
contractility in these pathophysiologies (de Belder et al. Br.
Heart. J. 4, 426-430, 1995).
[0090] In animal models of acute or chronic inflammation, blockade
of inducible NO-synthase by isoform-selective or nonselective
inhibitors or genetic knock out improves therapeutic outcome. It is
reported that experimental arthritis (Connor et al. Eur. J.
Pharmacol. 273, 15-24, 1995) and osteoarthritis (Pelletier et al.
Arthritis & Rheum. 41, 1275-1286, 1998), experimental
inflammations of the gastrointestinal tract (Zingareill et al. Gut
45, 199-209.1999), experimental glomerulonephritis (Narita et al.
Lab. Invest 72, 17-24, 1995), experimental diabetes (Corbett et al.
PNAS 90, 8992-8995, 1993), LPS-induced experimental lung injury is
reduced by inhibition of inducible NO-synthase or in iNOS-knock out
mice (Kristof et al. Am. J. Crit. Care. Med. 158, 1883-1889, 1998).
A pathophysiological role of inducible NO-synthase derived NO or
O.sub.2.sup.- is also discussed in chronic inflammatory diseases
such as asthma, bronchitis and COPD.
[0091] Furthermore, in models of neurodegenerative diseases of the
CNS such as MPTP-induced parkinsonism, amylold peptide induced
Alzheimer's disease (Ishii et al., FASEB J. 14, 1485-1489, 2000),
malonate induced Huntington's disease (Connop et al.
Neuropharmacol. 35,459-465, 1996), experimental menengitis (Korvtko
& Boje Neuropharmacol. 35, 231-237, 1996) and experimental
encephalitis (Parkinson et al. J. Mol. Med. 75, 174-186, 1997) a
causal participation of NO and inducible NO-synthase has been
shown.
[0092] Increased iNOS expression has been found in the brains of
AIDS victims and it is reasonable to assume a role of iNOS in AIDS
related dementia (Bagasra et al. J. Neurovirol. 3 153-167,
1997).
[0093] Other studies implicated nitric oxide as a potential
mediator of microglia dependent primary demyelination, a hallmark
of multiple sclerosis (Parkinson et al. J. Mol. Med. 75, 174-186,
1997).
[0094] An inflammatory reaction with concomitant expression of
inducible NO-synthase also takes place during cerebral ischemia and
reperfusion (Iadecola et al. Stroke 27, 1373-1380, 1996). Resulting
NO together with O.sub.2.sup.- from infiltrating neutrophils is,
thought to be responsible for cellular and organ damage.
[0095] Also, in models of traumatic brain injury (Mesenge et al. J.
Neurotrauma 13, 209-214, 1996; Wada et al. Neurosurgery-43,
1427-1436, 1998) NO-synthase inhibitors have been show to posses
protective properties. A regulatory role for inducible NO-synthase
has been reported in various tumor cell lines (Tozer & Everett
Clin Oncol. 9. 357-264, 1997).
[0096] On account of their inducible NO-synthase-inhibiting
properties, the compounds according to the invention can be
employed in human and veterinary medicine and therapeutics, where
an excess of NO or O.sub.2.sup.- due to increases in the activity
of inducible NO-synthase is involved. They can be used without
limitation for the treatment and prophylaxis of the following
diseases:
[0097] Acute inflammatory diseases: Septic shock, sepsis, SIRS,
hemorrhagic shock, shock states induced by cytokine therapy (IL-2,
TNF), organ transplantation and transplant rejection, head trauma,
acute lung injury, ARDS, inflammatory skin conditions such as
sunburn, inflammatory eye conditions such as uveitis, glaucoma and
conjunctivitis.
[0098] Chronic inflammatory diseases of peripheral organs and the
CNS: gastrointestinal inflammatory diseases such as Crohn's
disease, Inflammatory bowel disease, ulcerative colitis, lung
inflammatory diseases such as asthma and COPD, arthritic disorders
such as rheumatoid arthritis, osteoarthritis and gouty arthritis,
heart disorders such as cardiomyopathy and myocarditis,
artherosklerosis, neurogenic inflammation, skin diseases such as
psoriasis, dermatitis and eczema, diabetes, glomerulonephritis;
dementias such as dementias of the Alzheimer's type, vascular
dementia, dementia due to a general medical condition, such as
AIDS, Parkinson's disease, Huntngton's induced dementias, ALS,
multiple sclerosis; necrotizing vasculitides such as polyarteritis
nodosa, serum sickness, Wegener's granulomatosis, Kawasaki's
syndrom; headaches such as migraine, chronic tension headaches,
cluster and vascular headaches, post-traumatic stress disorders;
pain disorders such as neuropathic pain; myocardial and cerebral
ischemia/reperfusion injury.
[0099] The compounds may also be useful in the treatment of cancers
that express nitric oxide synthase.
[0100] The invention further relates to a method for the treatment
of mammals, including humans, which are suffering from one of the
abovementioned illnesses. The method is characterized in that a
therapeutically active and pharmacologically effective and
tolerable amount of one or more of the compounds according to the
invention is administered to the ill mammal.
[0101] The invention further relates to the compounds according to
the invention for use in the treatment and/or prophylaxis of
illnesses, especially the illnesses mentioned.
[0102] The invention also relates to the use of the compounds
according to the invention for the production of pharmaceutical
compositions which are employed for the treatment and/or
prophylaxis of the illnesses mentioned.
[0103] The invention also relates to the use of the compounds
according to the invention for the production of pharmaceutical
compositions having an iNOS inhibitory activity.
[0104] The invention furthermore relates to pharmaceutical
compositions for the treatment and/or prophylaxis of the illnesses
mentioned, which contain one or more of the compounds according to
the invention.
[0105] The invention moreover relates to pharmaceutical
compositions according to this invention having an iNOS inhibitory
activity.
[0106] The pharmaceutical compositions are prepared by processes
which are known per se and familiar to the person skilled in the
art. As pharmaceutical compositions, the compounds according to the
invention (=active compounds) are either employed as such, or
preferably in combination with suitable pharmaceutical auxiliaries
and/or excipients, e.g. in the form of tablets, coated tablets,
capsules, caplets, suppositories, patches (e.g. as TTS), emulsions,
suspensions, gels or solutions, the active compound content
advantageously being between 0.1 and 95% and where, by the
appropriate choice of the auxiliaries and/or excipients, a
pharmaceutical administration form (e.g. a delayed release form or
an enteric form) exactly suited to the active compound and/or to
the desired onset of action can be achieved.
[0107] The person skilled in the art is familiar with auxiliaries
or excipients which are suitable for the desired pharmaceutical
formulations on account of his/her expert knowledge. In addition to
solvents, gel formers, ointment bases and other active compound
excipients, for example antioxidants, dispersants, emulsifiers,
preservatives, solubilizers, colorants, complexing agents or
permeation promoters, can be used.
[0108] The administration of the pharmaceutical compositions
according to the invention may be performed in any of the generally
accepted modes of administration available in the art. Illustrative
examples of suitable modes of administration include intravenous,
oral, nasal, parenteral, topical, transdermal and rectal delivery.
Oral and intravenous delivery are preferred.
[0109] For the treatment of disorders of the respiratory tract, the
compounds according to the invention are preferably also
administered by inhalation in the form of an aerosol; the aerosol
particles of solid, liquid or mixed composition preferably having a
diameter of 0.5 to 10 .mu.m, advantageously of 2 to 6 .mu.m.
[0110] Aerosol generation can be carried out, for example, by
pressure-driven jet atomizers or ultrasonic atomizers, but
advantageously by propellant-driven metered aerosols or
propellant-free administration of micronized active compounds from
inhalation capsules.
[0111] Depending on the inhaler system used, in addition to the
active compounds the administration forms additionally contain the
required excipients, such as, for example, propellants (e.g. Frigen
in the case of metered aerosols), surface-active substances,
emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g.
lactose in the case of powder inhalers) or, if appropriate, further
active compounds.
[0112] For the purposes of inhalation, a large number of
apparatuses are available with which aerosols of optimum particle
size can be generated and administered, using an inhalation
technique which is as right as possible for the patient. In
addition to the use of adaptors (spacers, expanders) and
pear-shaped containers (e.g. Nebulator.RTM., Volumatic.RTM.), and
automatic devices emitting a puffer spray (Autohaler.RTM.), for
metered aerosols, in particular in the case of powder inhalers, a
number of technical solutions are available (e.g. Diskhaler.RTM.,
Rotadisk.RTM., Turbohaler.RTM. or the inhaler described in European
Patent Application EP 0 505 321), using which an optimal
administration of active compound can be achieved.
[0113] For the treatment of dermatoses, the compounds according to
the invention are in particular administered in the form of those
pharmaceutical compositions which are suitable for topical
application. For the production of the pharmaceutical compositions,
the compounds according to the invention (=active compounds) are
preferably mixed with suitable pharmaceutical auxiliaries and
further processed to give suitable pharmaceutical formulations.
Suitable pharmaceutical formulations are, for example, powders,
emulsions, suspensions, sprays, oils, ointments, fatty ointments,
creams, pastes, gels or solutions.
[0114] The pharmaceutical compositions according to the invention
are prepared by processes known per se. The dosage of the active
compounds is carded out in the order of magnitude customary for
iNOS Inhibitors. Topical application forms (such as ointments) for
the treatment of dermatoses thus contain the active compounds in a
concentration of, for example, 0.1-99%. The dose for administration
by inhalation is customarily between 0.1 and 10 mg per day. The
customary dose in the case of systemic therapy (p.o.) is between
0.3 and 30 mg/kg per day, (i. v.) is between 0.3 and 30
mg/kg/h.
Biological Investigations
Measurement of Inducible NO-synthase Activity
[0115] The assay is performed in 96-well microliter F-plates
(Greiner, Frickenhausen, FRG) in a total volume of 100 .mu.l in the
presence of 100 nM calmodulin, 226 .mu.M CaCl.sub.2, 477 .mu.M
MgCl.sub.2, 5 .mu.M flavin-adenine-dinucleotide (FAD), 5 .mu.M
flavin mononucleotide (FMN), 0.1 mM NADPH, 7 mM glutathione, 10
.mu.M BH4 and 100 mM HEPES pH 7.2. Arginine concentrations are 0.1
.mu.M for enzyme inhibition experiments. 150000 dpm of
[.sup.3H]arginine are added to the assay mixture. Enzyme reaction
is started by the addition of 4 .mu.g of a crude cytosolic fraction
containing human inducible NO-synthase and the reaction mixture is
incubated for 45 to 60 min at 37.degree. C. Enzyme reaction is
stopped by adding 10 .mu.l of 2M MES-buffer pH 5.0. 50 .mu.l of the
incubation mixture are transferred into a MADP N65 filtration
microtiter plate (Millipore, Eschbom, FRG) containing already 50
.mu.l of AG-50W-X8 cation exchange resin (Biorad, Munchen, FRG).
The resin in the Na loaded form is pre-equilibrated in water and 70
.mu.l (corresponding to 50 .mu.l dry beads) are pipetted under
heavy stirring with a 8 channel pipette into the filtration plate.
After pipetting 50 .mu.l of the enzyme reaction mixture onto the
filtration plates, the plates are placed on a filtration manifold
(Porvair, Shepperton, UK) and the flow through is collected in Pico
scintillation plates (Packard, Meriden, Conn.). The resin in the
filtration plates is washed with 75 ul of water (1.times.50 .mu.l
and 1.times.25 .mu.l) which is also collected in the same plate as
the sample. The total flow through of 125 .mu.l is mixed with 175
.mu.l of Microscint-40 scintillation cocktail (Packard) and the
scintillation plate is sealed with TopSeal P-foil (Packard).
Scintillation plates are counted in a scintillation counter.
[0116] For the measurement of inducible NO-synthase-inhibiting
potencies of compounds increasing concentrations of inhibitors were
included into the incubation mixture. IC.sub.50-values were
calculated from the percent inhibition at given concentrations by
nonlinear least square fitting.
[0117] The inhibitory values determined for the compounds according
to the invention follow from the following table A, in which the
compound numbers correspond to the example numbers.
TABLE-US-00002 TABLE A Inhibition of iNOS activity [measured as
-logIC.sub.50 (mol/l)] compound -logIC.sub.50 1 7.83 2 7.45 3 7.86
4 7.83 5 7.62 6 7.67
* * * * *