Bicyclic imidazo-5-yl-amine derivatives

Details Bicyclic imidazo-5-yl-amine derivatives Bicyclic imidazo-5-yl-amine derivatives

2002-04-08

2003-12-02

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S126000, C548S136000, C548S154000, C514S363000, C514S368000, C546S273100

Reexamination Certificate

active

06657064

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of international patent application no. PCT/EP00/09097, filed Sep. 18, 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 nos. 199 48 436.8, and 199 48 434.1, both filed Oct. 8, 1999.
BACKGROUND OF THE INVENTION
The present invention relates to substituted bicyclic imidazo-5-yl-amines and medicaments comprising these compounds.
Individual representatives from the class of bicyclic imidazo-5-yl-amines are described in EP-A-0 518 033. These compounds carry aromatic substituents bonded via a short alkyl bridge on the imidazole nitrogen which does not belong to the fused ring system. The compounds described in EP-A-0 518 033 as potent angiotensin antagonists which can be employed in medicaments for treatment of circulatory diseases such as high blood pressure.
Attempts have subsequently been made also to prepare those bicyclic imidazo-5-yl-amines which are not substituted on the imidazole nitrogen which does not belong to the fused ring system. However, these attempts had no (K. Groebke et al., Synlett 1998, 661) or only little success (H. Bienayme, K. Bouzid, Angew. Chem. 1998, 110 (16), 2349).
The present invention was therefore based on the object of providing bicyclic imidazo-5-yl-amines which are not substituted on the imidazole nitrogen which does not belong to the fused ring system, and medicaments comprising these compounds.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The invention therefore provides bicyclic imidazo-5-yl-amines of the general formula I
wherein
R
1
denotes C(CH
3
)
3
, (CH
2
)
6
CN, 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, C
1
-C
8
-alkyl (branched or unbranched), optionally substituted phenyl, CO(OR′) (where R′=C
1
-C
8
-alkyl (branched or unbranched)), PO(OR″)
2
(where R″=C
1
-C
4
-alkyl (branched or unbranched)) 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
8
-alkyl (branched or unbranched), C
4
-C
8
-cycloalkyl or phenyl),
R
2
denotes hydrogen; COR
b
, wherein R
b
represents hydrogen, C
1
-C
8
-alkyl (branched or unbranched), C
3
-C
8
-cycloalkyl, CH
2
CH
2
CO(OR′) (where R′=C
1
-C
8
-alkyl (branched or unbranched)), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH
2
R
c
, wherein R
c
represents hydrogen, C
1
-C
8
-alkyl (branched or unbranched) or optionally substituted phenyl; CH
2
CH
2
R
d
, wherein R
d
represents optionally substituted phenyl; or CONHR
e
, wherein R
e
represents phenyl,
R
3
denotes C
1
-C
8
-alkyl (branched or unbranched), C
3
-C
8
-cycloalkyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, phenanthrene, benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene,
X denotes CR
5
, N or S, and
Y, in the case where X denotes S, denotes CR
6
or N, and in all other cases denotes N,
wherein the broken line in the structural element:
 means that in the cases where X denotes S, Y is linked via a double bond with the C atom carrying R
4
, and in all other cases one of the groups X or Y is linked via a double bond with the C atom carrying R
4
and the other particular group carries an additional hydrogen,
R
4
, R
5
and R
6
independently of one another denote hydrogen, C
1
-C
8
-alkyl (branched or unbranched); fluorine; chlorine; bromine; CF
3
; CN; NO
2
, NHR
f
, wherein R
f
represents hydrogen, C
1
-C
8
-alkyl (branched or unbranched) or optionally substituted phenyl; SR
g
, wherein R
g
represents hydrogen, C
1
-C
8
-alkyl (branched or unbranched), phenyl, pyridine, benzyl or fluorenyl; OR
h
, wherein R
h
represents C
1
-C
8
-alkyl (branched or unbranched), optionally substituted phenyl or CO(OR′) (R′=C
1
-C
8
-alkyl (branched or unbranched)); CO(OR′) or CH
2
CO(OR′), wherein R′ in each case has the abovementioned meaning or in the case of the group CH
2
CO(OR′) also denotes hydrogen, or an optionally substituted phenyl group; and pharmaceutically acceptable salts thereof,
excluding compounds in which either at the same time R
1
denotes C(CH
3
)
3
, R
2
denotes hydrogen, R
3
denotes unsubstituted phenyl, X denotes S and Y denotes N or CR
6
, where R
6
=hydrogen or CH
2
—CO
2
-ethyl, or at the same time R
1
denotes C(CH
3
)
3
, R
2
denotes hydrogen, R
3
denotes unsubstituted phenyl, Y denotes NH and X denotes N or CR
5
, where R
5
═CO
2
ethyl.
Optionally substituted phenyl, optionally substituted 1-naphthyl, optionally substituted pyrrole, optionally substituted furfuryl, optionally substituted thiophene, optionally substituted isocyanate and optionally substituted alkyl, according to the instant invention, may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, cyano group, nitro group, carboxyl group, hydroxyl group, C
1
-C
4
alkylamido group, C
1
-C
4
alkylamino group, pyrrolidino group, branched or unbranched C
1
-C
6
alkyl group, C
1
-C
4
alkyl group substituted with one or more halogen atoms, C
1
-C
4
alkoxy group, C
1
-C
4
alkoxy group substituted with one or more halogen atoms, and halogen substituted phenoxy group.
Where R
3
is a substituted phenyl group, it is preferably 4-acetamidophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 4-tert-butylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-cyanophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-hexylphenyl, 3-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 3-phenoxyphenyl, 4-(1-pyrrolidino)phenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3,4,5-trimethoxyphenyl, 3-(4-chlorophenoxy)phenyl or 4-acetoxy-3-methoxyphenyl.
Where R
3
is a substituted 1-naphthyl group, it is preferably 4-dimethylaminonaphthyl, 2-ethoxynaphthyl or 4-methoxynaphthyl.
Where R
3
is a substituted pyrrole group, it is preferably 2-(1-(phenylsulfonyl)-pyrrole), 2-(N-methylpyrrole), 2-(N-(3,5-dichlorophenyl)-pyrrole or 2-(1-(4-chlorophenyl)pyrrole).
Where R
3
is a substituted furfuryl group, it is preferably 2-(5-acetoxymethylfurfuryl), 2-(5-methylfurfuryl), 2-(5-nitrofurfuryl), 2-[5-(3-nitrophenyl)furfuryl], 2-[5-(2-nitrophenyl)furfuryl], 2-(5-bromofurfuryl), 2-[5-(4-chlorophenyl)furfuryl], 2-(4,5-dimethylfurfuryl), 2-[5-(2-chlorophenyl)furfuryl], 2-(5-ethylfurfuryl) or 2-[5-(1,3-dioxalane)furfuryl].
Where R
3
is a substituted thiophene group, it is preferably 2-(5-chlorothiophenyl), 2-(5-methylthiophenyl), 2-(5-ethylthiophenyl), 2-(3-methylthiophenyl), 2-(4-bromothiophenyl), 2-(5-nitrothiophenyl), 5-(2-carboxythiophenyl), 2-[4-(phenylethyl)thiophenyl], 2-[5-(methylthio)thiophenyl], 2-(3-bromothiophenyl), 2-(3-phenoxythiophenyl) or 2-(5-bromothiophenyl).
Where R
b
is a substituted phenyl group, it is preferably 3,5-bis(trifluoromethyl)phenyl, 2-bromophenyl, 2-fluorophenyl, pentafluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2-acetylphenyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 2-(trifluoromethyl)phenyl, 2-methylphenyl, 3-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl, 3-(trifluoromethyl)ph

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