Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-08
2004-03-09
Haung, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S121000
Reexamination Certificate
active
06703404
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of international patent application no. PCT/EP00/09791, filed Oct. 6, 2000, designating the United States of America, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany patent application no. 199 48 434.1, filed Oct. 8, 1999.
BACKGROUND OF THE INVENTION
This invention relates to tert.-butyl-(7-methyl-imidazo[1,2-a]pyridin-3-yl)-amine derivatives, to a method of producing them, to drugs which contain these compounds, to methods for inhibiting NO synthase and for the treatment of migraine, etc., using the tert.-butyl-(7-methyl-imidazo[1,2-a]pyridin-3-yl)-amine derivatives according to the invention and also relates to pharmaceutical compositions which contain tert.-butyl(7-methyl-imidazo[1,2-a]pyridin-3-yl)-amine derivatives.
Nitrogen monoxide (NO) regulates numerous physiological processes, including neurotransmission, the relaxation and proliferation of smooth musculature, the adhesion and aggregation of thrombocytes, as well as tissue damage and inflammation, amongst others. Due to its multiplicity of signal functions, NO is associated with a whole series of diseases (see L. J. Ignarro,
Angew. Chem
. (1999). 111, 2002-2013 and F. Murad.
Angew. Chem. Int. Ed
. (1999), 111, 1976-1989, for example). The enzyme which is responsible for the physiological formation of NO, namely NO synthase (NOS), thus plays an important part in the effect of therapy on these diseases. Three different isoforms of NO synthase, namely the two constituent nNOS and eNOS, as well as the inducable form INOS, have hitherto been identified (A. J. Hobbs. A. Higgs, 5. Moncada.
Annu. Rev. Pharmacol. Toxicol
. (1999), 39, 191-220; I. C. Green, P. -E. Chabrier, DDT(1999), 4, 47-49; P. -E. Chabrier et al.
Cell. Mol. Life Sci
. (1999), 55, 1029-1035).
The inhibition of NO synthase opens up new approaches to therapy for various diseases which are associated with NO (A. J. Hobbs et al.
Annu. Rev.Pharmacol Toxicol
. (1999), 39, 191-220; I. C. Green. P. -E. Chabrier, DDT (1999), 4, 47-49: P. -E. Chabrier et al.,
Cell. Mol. Life Sci
. (1999), 55, 1029-1035), such as migraine (L. L. Thomsen. J. Olesen.
Clinical Neuroscience
(1998), 5, 28-33; L. H. Lassen et al.,
The Lancet
(1997), 349, 401-402), septic shock, neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease, inflammation, pain due to inflammation, cerebral ischaemia, diabetes, meningitis and arteriosclerosis. Furthermore, NOS inhibition can also have an effect on the healing of wounds, on tumours and on angiogenesis, as well as giving rise to non-specific immunity in relation to microorganisms (A. J. Hobbs et al.
Annu. Rev. Pharmacol. Toxicol
. (1999), 39, 191-220).
Apart from N
G
-monomethyl-L-arginine (L-NMMA) and N
W
-nitro-L-arginine methylester (L-NAME)—i.e. analogues of L-arginine from which NO and citrulline are formed in vivo with the participation of NOS, the active ingredients known hitherto which inhibit NO synthase are S-methyl-L-citrullin, aminoguanidine, S-methylisourea, 7-nitromidazole and 2-mercaptoethylguanidine, etc., (A. J. Hobbs et al.,
Annu. Rev. Pharmacol. Toxicol
. (1999), 39, 191-220).
In contrast, the underlying object of the present invention was to provide new, effective NOS inhibitors.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
It has surprisingly been found that 3-tert.-butyl-amino-substituted imidazo[1,2-a]pyridines of general structure I
wherein
R
1
denotes H or a C
1-4
alkanyl, wherein the alkanyl is straight-chain or branched and is unsubstituted or singly- or multiply-substituted, and
R
2
denotes a C
1-8
alkyl, wherein the alkyl is straight-chain or branched, is saturated or unsaturated and is unsubstituted or singly- or multiply-substituted, a C
3-8
cycloalkyl, wherein the cycloalkyl is saturated or unsaturated and is unsubstituted or singly- or multiply-substituted, a heterocyclyl, wherein the heterocyclyl is saturated or unsaturated and is unsubstituted or singly- or multiply-substituted, an aryl, wherein the aryl is unsubstituted or singly or multiply-substituted, a heteroaryl, wherein the heteroaryl is unsubstituted or singly or multiply-substituted, a C
1-8
alkyl-C
3-8
cycloalkyl, a C
1-5
alkyl-heterocyclyl, a C
1-8
alkyl-aryl or a C
1-6
alkyl-heteroaryl, wherein the alkyl is straight-chain or branched, is saturated or unsaturated and is unsubstituted or singly or multiply-substituted, the cycloalkyl is saturated or unsaturated and is unsubstituted or singly or multiply-substituted, the heterocyclyl is saturated or unsaturated and is unsubstituted or singly- or multiply-substituted, the aryl is unsubstituted or singly- or multiply-substituted, and the heteroaryl is unsubstituted or singly- or multiply-substituted,
in the form of their bases or of one of their pharmaceutically acceptable salts, constitute very effective NOS inhibitors.
These compounds as such are new, with the exception of the 3-tert.-butyl-amino-substituted imidazo[1,2-a]pyridine of general structure I wherein R
1
=methyl and R
2
=phenyl, which has been described by H. Bienyme and K. Bouzid in
Angew. Chem
1998), 110, 2349-2352, although without the disclosure of an NOS inhibiting effect (or any other pharmacological or therapeutic effect). Therefore, the present invention also relates to this last-mentioned compound insofar as it relates to the use thereof in a drug, particularly for producing a medication for the inhibition of NO synthase and for the treatment of migraine, septic shock, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammation, pain due to inflammation, cerebral ischaemia, meningitis, arteriosclerosis and/or for the healing of wounds, and insofar as it relates to a pharmaceutical composition containing said compound.
In the sense of this invention, the expression “C
1-8
alkyl” comprises acyclic, saturated or unsaturated hydrocarbon radicals which can be branched- or straight-chain and which can be unsubstituted or singly- or multiply-substituted, containing 1 to 8 C atoms, i.e. C
1-8
alkanyls, C
2-8
alkenyls and C
2-8
alkynyls. The alkenyls contain at least one C—C double bond and the alkynyls contain at least one C—C triple bond. The alkyls are advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-octyl, ethylenyl (vinyl), ethynyl, propenyl (—CH
2
CH═CH
2
, —CH═CH—CH
3
, —C(═CH
2
)—CH
3
), propynyl (—CH—C≡CH, —C≡C—CH
3
), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, octenyl and octynyl.
In connection with the present invention, the expression “C
1-4
alkanyl” comprises saturated, acyclic hydrocarbon radicals containing with 1 to 4 carbon atoms, wherein the radicals are straight-chain or branched and are unsubstituted or singly- or multiply-substituted. The C
1-4
alkanyl is advantageously methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl or tert.-butyl. C
1-4
alkanyl most preferably represents methyl.
For the purposes of this invention, the expression “C
3-8
cycloalkyl” denotes cyclic hydrocarbons containing 3 to 8 carbon atoms, which can be saturated or unsaturated, unsubstituted or singly- or multiply-substituted. C
3-8
cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl. cyclohexenyl, cycloheptenyl and cyclooctenyl. Cycloalkyl most preferably represents cyclohexyl.
The expression “heterocyclyl” represents a 3-, 4-, 5-, 6- or 7-membered cyclic organic radical which contains at least 1 hetero atom, or which optionally even contains 2, 3, 4 or 5 hetero atoms, wherein the hetero atoms are identical or different and the cyclic radical is saturated or unsaturated but is not a
Gerlach Matthias
Hennies Hagen-Heinrich
Maul Corinna
Schneider Johannes
Sundermann Bernd
Crowell & Moring LLP
Gruenenthal GmbH
Haung Evelyn Mei
LandOfFree
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