Bicyclic imidazo-3-yl-amine derivatives

Details Bicyclic imidazo-3-yl-amine derivatives Bicyclic imidazo-3-yl-amine derivatives

2002-04-08

2003-10-28

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S265100, C514S300000, C544S281000, C544S350000, C546S121000

Reexamination Certificate

active

06638933

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to substituted bicyclic imidazo-3-yl-amines and medicaments comprising these compounds.
Interesting pharmacological properties are known for individual compounds from the class of imidazo-3-yl-amines. Thus, certain imidazo[1,2-a]pyridines are known as active compounds which lower blood pressure (GB-B-1,135,893), as anthelmintics and antimycotics (
J. Med. Chem.
1972, 15, 982-985), and as antisclerotic active compounds for the treatment of inflammatory diseases (EP-A-0 068 378). EP-A-0 266 890 and
J. Med. Chem.
1987, 30, 2031-2046 also describe an action of individual imidazopyridines against inflammatory diseases, in particular of the stomach. Further pharmacological actions described for individual representatives from the class of imidazo-3-yl-amines are antibacterial properties (
Chem. Pharm. Bull.
1992, 40, 1170), antiviral properties (
J. Med. Chem.
1998, 41, 5108-5112) and the action as a benzodiazepine receptor antagonist (
J. Heterocyclic Chem.
1998, 35, 1205-1217).
In view of these interesting actions, various representatives from the class of substituted imidazo-3-yl-amines have been synthesized in the past. In particular, attempts have been made to increase the number of substituted imidazo-3-yl-amines available by combinatory synthesis processes. Thus, C. Blackburn et al. describe a three-component solid phase synthesis for the preparation of imidazo-3-yl-amines in
Tetrahedron Lett.
1998, 39, 5469-5472 and a three-component condensation for parallel synthesis of imidazo-3-yl-amines in
Tetrahedron Lett.
1998, 39, 3635-3638. The synthesis published by K. Groebke et al. in
Synlett
1998, 661-663 is similar to the latter reaction. A multi-component reaction for combinatory synthesis of imidazo-3-yl-amines, with which individual imidazo-5-amines have also been prepared, is also described by H. Bienayme and K. Bouzid in
Angew. Chem.
1998, 110 (16), 2349-2352.
However, the range of variation possible according to the prior art for the substituents on the amino nitrogen and in the 2-position of the imidazole ring was limited.
The present invention was therefore based on the object of providing further bicyclic imidazo-3-yl-amines, and medicaments comprising these compounds.
The invention therefore provides bicyclic imidazo-3-yl-amines of general formula I
wherein
X and Y denote CH or N, with the proviso that X and Y do not simultaneously denote N,
R
1
denotes tert-butyl, (CH
2
)
n
CN, where n=4, 5 or 6, optionally substituted phenyl, C
4
-C
8
-cycloalkyl, CH
2
CH
2
R (R=4-morpholino), 1,1,3,3-tetramethylbutyl or CH
2
R
a
, wherein R
a
represents hydrogen, OH, C
1
-C
8
-alkyl (branched or unbranched), optionally substituted phenyl, CO(OR′) (where R′=unbranched C
1
-C
4
-alkyl or branched C
1
-C
5
-alkyl), PO(OR′)
2
(where R′=unbranched C
1
-C
4
-alkyl or branched C
1
-C
5
-alkyl) or Si(R
x
R
y
R
z
) (where R
x
, R
y
, and R
z
in each case independently of one another are C
1
-C
4
-alkyl (branched or unbranched), C
4
-C
8
-cycloalkyl or phenyl);
R
2
denotes hydrogen, COR
b
, wherein R
b
represents C
1
-C
4
-alkyl (branched or unbranched) or C
3
-C
8
-cycloalkyl, CH
2
CH
2
CO(OR
c
), wherein R
c
represents C
1
-C
4
-alkyl (branched or unbranched), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl or 2-naphthyl or in each case optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH
2
-phenyl, CH
2
CH
2
R
d
, wherein R
d
represents optionally substituted phenyl, or CONHR
e
, wherein R
e
represents C
1
-C
8
-alkyl (branched or unbranched), C
3
-C
8
-cycloalkyl or optionally substituted phenyl;
R
3
denotes methyl, ethyl, tert-butyl, C
3
-C
8
-cycloalkyl, phenyl, optionally monosubstituted in the 3-, 5- or 6-position or optionally polysubstituted in the 4-position and additionally in the 2- and/or 3- and/or 5- and/or 6-position, phenoxy, optionally substituted naphthyl, optionally substituted pyrrole, optionally substituted pyridyl, optionally substituted furan, optionally substituted thiophene, optionally substituted anthracene, optionally substituted phenanthrene or optionally substituted quinoline,
with the proviso that R
3
does not denote n-propyl, cyclohexyl, unsubstituted phenyl or phenyl monosubstituted in the 3-position with a carboxylic acid amide group if R
1
denotes t-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, CH
2
CH
2
R (R=4-morpholino), monosubstituted phenyl, 2,6-dimethylphenyl or benzyl and at the same time R
2
denotes hydrogen or —CO(methyl), and that R
2
does not denote hydrogen if at the same time R
1
denotes benzyl and R
3
denotes methyl, or at the same time R
1
denotes CH
2
C(O)tert-butyl and R
3
denotes unsubstituted phenyl; in the form of at least one base or of at least one pharmaceutically acceptable salt.
Preferred compounds according to the invention are those in which R
2
denotes hydrogen; R
1
is selected from the group consisting of (CH
2
)
n
CN, where n=4, 5 or 6, cyclohexyl, CH
2
CO(O-methyl), 2,6-dimethylphenyl, 1,1,3,3-tetramethylbutyl, tert-butyl or n-butyl; and R
3
is selected from the group consisting of 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrroyl, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-dimethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3-bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-fluorophenyl, 3-methylphenyl, 3-phenoxyphenyl, 3-(4-chlorophenoxy)phenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-bromophenyl, 2-fluorophenyl, or 2-(trifluoromethyl)-phenyl.
Compounds which are particularly preferred according to the invention are bicyclic imidazo-3-yl-amines selected from the group consisting of
(6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano-hexyl)-amine,
(2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano-hexyl)-amine,
(2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
(2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester,
(2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino)-acetic acid methyl ester,
(2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester,
(2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine,
(2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine,
3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl)-phenol, butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-amine,
[(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl]-phosphonic acid diethyl ester,
tert-butyl-(2-tert-butyl-imidazo [1,2-a]pyridin-3-yl)-amine,
butyl-(2-o-tolyl-imidazo [1,2-a]pyrimidin-3-yl)-amine,
(2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-amine,
butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
tert-butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine,
[2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine,
N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-acetamide,
tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-amine,
[2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-cyclohexyl-amine, ace

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