Imidazole derivatives

Details Imidazole derivatives Imidazole derivatives

2001-01-12

2002-05-14

Solola, T. A. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S312100, C514S396000, C514S397000, C514S399000

Reexamination Certificate

active

06388090

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to new pharmacologically active imidazole derivatives and pharmaceutically acceptable salts and esters thereof, as well as to processes for their preparation and to pharmaceutical compositions containing them.
It is known that several derivatives of imidazole have affinity for alpha1 and/or alpha2 adrenoceptors. Accordingly, WO-A-97 12874 describes imidazole-substituted (1,2,3,4-tetrahydro-1-naphthalenyl)- and (2,3-dihydro-1H-inden-1-yl)-derivatives which are stated to possess affinity for alpha2 adrenoceptors, most of them being selective alpha2 adrenoceptor agonists. EP-A-0 717 037 describes 4-(1,2,3,4-tetrahydro-1-naphthalenyl)- and 4-(2,3-dihydro-1H-inden-1-yl)-1H-imidazole derivatives which possess alfa2 adrenoceptor agonistic and alpha1 adrenoceptor antagonistic activity. On the other hand, the imidazole derivatives disclosed in EP-A-0 183 492 are known as selective alpha2 adrenoceptor antagonists. Compounds acting on the said alpha adrenoceptors may exert a wide variety of peripheral and/or CNS (central nervous system) effects in mammals.
SUMMARY OF THE INVENTION
The inventors have now found that the present imidazole derivatives of the invention exhibit affinity for alpha2 adrenoceptors so that they can be useful in the treatment of various disorders or diseases wherein the alpha2 adrenoceptors are involved. Such disorders or diseases include various disorders of the central nervous system (CNS), i.e. neurological, psychiatric or cognition disorders, as well as various disorders of the pheripheric system, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
DETAILED DESCRIPTION OF THE INVENTION
The imidazole derivatives of the invention can be represented by the following formula (I):
wherein
X is —CH
2
—(CH
2
)
p
—, —O—, ═NH or —S—;
R
1
is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, C
3
-C
7
-cycloalkyl, C
5
-C
7
-cycloalkenyl, C
5
-C
7
-cycloalkynyl or mono- or bicyclic aromatic or partially or fully saturated heterocyclic group with 5 to 10 ring atoms which consist of carbon atoms and one to three heteroatoms selected from N, O and S;
wherein the said phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, C
3
-C
7
-cycloalkyl, C
5
-C
7
-cycloalkenyl, C
5
-C
7
-cycloalkynyl or mono- or bicyclic aromatic or partially or fully saturated heterocyclic group is optionally substituted with one to three substituents selected independently from halogen, —OH, —NH
2
, halo-C
1
-C
6
-alkyl, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
1
-C
6
-alkoxy, OH—(C
1
-C
6
)-alkyl, NH
2
—(C
1
-C
6
)-alkyl and mono- or di(C
1
-C
6
-alkyl)amino;
R
2
is H or C
1
-C
6
-alkyl;
R
3
is H or C
1
-C
6
-alkyl; and
R
4
is H or C
1
-C
6
-alkyl;
R
5
is H, or R
5
and R
7
form together a bond;
each R
6
is independently halogen, —OH, —NH
2
, halo-C
1
-C
6
-alkyl, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy or OH—(C
1
-C
6
)-alkyl;
R
7
is H, OH or C
1
-C
4
-alkyl, or R
7
and R
5
form together a bond;
each R
8
is independently OH, C
1
-C
6
-alkyl, halo-C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy;
m is 0,1,2 or 3;
n is 0 or 1;
p is 0 or 1;
r is 0 or 1;
t is 0,1 or 2;
or pharmaceutically acceptable esters or salts thereof.
When X is —CH
2
—(CH
2
)
p
— and p is 0, or when X is ═NH,
then the bulky substituent —(CR
2
R
3
)r— R
1
is preferably at the 2- or 3-position of the 5-ring moiety (whereby, of course, in the above formulae the H-atom attached to ring carbon atom or, respectively, ring nitrogen atom will be replaced by the said substituent).
When X is —CH
2
—(CH
2
)
p
— and p is 1,
then the bulky substituent —(CR
2
R
3
)r—R
1
is preferably at the 3- or 4-position of the 6-ring moiety.
The following subgroups (1) to (17) of compounds of formula I taken alone or in any combination with each other are preferred:
1) n is 0;
2) n is 1;
3) n is 1 and R
4
and R
5
are H;
4) r is 0;
5) r is 1 and R
2
and R
3
are independently H or C
1
-C
4
-alkyl; preferably H;
6) t is 0;
7) R
7
is H;
8) X is —CH
2
—(CH
2
)
p
—; and p is 0 or 1;
9) X is —CH
2
—(CH
2
)
p
— and p is 0;
10) X is —CH
2
—(CH
2
)
p
— and p is 1;
11) X is —O—;
12) R
1
is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, C
5
-C
7
-cycloalkyl, C
5
-C
7
-cycloalkenyl, C
5
-C
7
-cycloalkynyl, pyridyl, pyrimidinyl, thienyl, furyl, cyclohexyl, piperidyl, piperazinyl or morpholinyl; preferably R
1
is phenyl, naphthyl, pyridyl, thienyl, furyl or cyclohexyl; e.g. R
1
is phenyl; or e.g. R
1
is cyclohexyl;
13) R
1
is as defined above in subgroup (12) substituted with one to three of the substituents selected independently from halogen, —OH, —NH
2
, halo-C
1
-C
6
-alkyl, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl and C
1
-C
6
-alkoxy; preferably with one to three, e.g. one or two, of the substituents selected independently from halogen, —OH, C
1
-C
6
-alkoxy and C
1
-C
6
-alkyl; more preferably from F, —OH and C
1
-C
6
-alkoxy;
14) m is 0; or m is 1 or 2;
15) m is 1 or 2 and each R
6
is independently halogen, —OH, C
1
-C
6
-alkoxy or C
1
-C
6
-alkyl; preferably F, —OH or C
1
-C
6
-alkoxy;
16) n is 0 and X is —CH
2
—(CH
2
)
p
—; and/or
17) n is 1 and X is —CH
2
—(CH
2
)
p
—, —O—, ═NH or —S—, e.g. —CH
2
—(CH
2
)
p
— or —O—.
Preferred subgroups of compounds of formula I are, for example,
wherein R
1
to R
8
, m, n, r and t are as defined above.
In a subgroup of the compounds of formula I, IA or IB, r is 0, or r is 1 and R
2
and R
3
are H. In a further subgroup of the compounds of formula I, IA or IB, n is 0, or n is 1 and R
4
, R
5
and R
7
are H. Preferably, t is 0. The optional substituent R
6
is e.g. at 5- and/or 6-position of the indane ring system.
In a further preferred subgroup of the compounds I, IA or IB, R
1
is phenyl, naphthyl, pyridyl, thienyl, furyl or cyclohexyl, e.g. phenyl, pyridyl or cyclohexyl, such as phenyl or cyclohexyl, e.g. phenyl, each of which is optionally substituted with one to three, e.g. one or two, of the substituents selected independently from halogen, —OH, —NH
2
, halo-C
1
-C
6
-alkyl, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
1
-C
6
-alkoxy, OH—(C
1
-C
6
)-alkyl, NH
2
—(C
1
-C
6
)-alkyl and mono- or di(C
1
-C
6
-alkyl)amin; e.g. from halogen, —OH, C
1
-C
6
-alkoxy and C
1
-C
6
-alkyl; preferably from F, —OH and C
1
-C
6
-alkoxy.
In a further preferred subgroup of the compounds I, IA or IB m is 0, or m is 1 or 2 and each R
6
is independently halogen, —OH or C
1
-C
6
-alkoxy.
A further subgroup of the compounds of formula I are compounds of formula IC or ID
wherein R
1
to R
8
, m, n, r and t are as defined above.
A further subgroup of the compounds of formula I are compounds of formula IE
wherein R
1
to R
8
, m, n and r are as defined above and t is 0 or 1.
Terms as employed herein have the following meanings: A halogen or halo is e.g. fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine. The term C
1
-C
6
-alkyl group as employed herein as such or as part of another group includes both straight and branched chain radicals of up to 6 carbon atoms, and preferably of 1 to 4 carbon atoms. The term C
1
-C
6
-alkoxy refers to —O(C
1
-C
6
-alkyl) wherein C
1
-C
6
-alkyl is as defined above. The term C
2
-C
6
-alkenyl includes both straight and branched chain radicals of up to 6 carbon atoms, preferably of 2 to 4 carbon atoms, containing double bond(s). The term C
2
-C
6
-alkynyl includes both straight and branched chain radicals of up to 6 carbon atoms, preferably of 2 to 4 carbon atoms, containing triple bond(s). The term halo- C
1
-C
6
-alkyl refers to C
1
-C
6
-alkyl radical, as defined above, that is substituted by one or more halo radicals as defined above, e.g. trifluoromethyl, difluoromethyl etc. The term C
3
-C
7
-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. C
5
-C
7
-cycloalkyl means cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopentyl or cyclohexyl. C
5
-C
7
-cycloalkenyl or C
5
-C
7
-cycloalkynyl refers to C
5
-C
7
-cycloalkyl as defined above, containing double bond(s) or, re

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