Polycyclic indanylimidazoles with alpha2 adrenergic activity

Details Polycyclic indanylimidazoles with alpha2 adrenergic activity Polycyclic indanylimidazoles with alpha2 adrenergic activity

2001-05-07

2002-03-26

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S399000, C548S341100, C548S345100

Reexamination Certificate

active

06362211

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to new pharmacologically active polycyclic indanylimidazole derivatives and pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical compositions containing them.
It is known that several derivatives of imidazole have affinity for alpha1 and/or alpha2 adrenoceptors. Accordingly, for example, 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. Furthermore, the imidazole derivatives disclosed in EP-A-0 183 492 are known as 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 polycyclic indanylimidazole derivatives of the invention exhibit affinity for alpha2 adrenoceptors so that they can be useful in the treatment of various diseases or conditions wherein the alpha2 adrenoceptors are involved. Such diseases or conditions include various disorders of the central nervous system (CNS), i.e. neurological, psychiatric or cognition disorders, as well as various disorders of the peripheric system, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
DETAILED DESCRIPTION OF THE INVENTION
The polycyclic indanylimidazole derivatives of the invention can be represented by the following formula (I):
wherein
—A— forms, together with the two carbon atoms to which it is attached, a ring system being a partially or fully saturated monocyclic carbocyclic ring of 3 to 7 ring atoms or a partially or fully saturated bicyclic bridged carbocyclic ring of 6 to 10 ring atoms, wherein each of the said ring systems formed by —A— is optionally fused with a benzene ring which is optionally substituted with one to three substituent(s) R
1
;
each R
1
is independently halogen, OH, NH
2
, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl, (C
1-6
)alkoxy, halo-(C
1-6
)alkyl, OH—(C
1-6
)alkyl, mono- or di(C
1-6
)alkylamino or OH—(C
1-6
)alkoxy(C
1-6
)alkoxy;
each R
2
is independently halogen, OH, ═O, ═CH
2
, NH
2
, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxy, halo-(C
1-6
)alkyl, OH—(C
1-6
)alkyl, NH
2
—(C
1-6
)alkyl or mono- or di(C
1-6
)alkylamino;
R
3
is H, F, OH, ═O, ═CH
2
, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl, (C
1-6
)alkoxy, halo-(C
1-6
)alkyl, NH
2
or mono- or di(C
1-6
)alkylamino;
m is 0, 1, 2 or 3; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable ester or salt thereof.
The invention also includes mixtures of compounds defined above.
In one possible subgroup of compounds of formula (I), the said ring formed by —A— is a fully saturated monocyclic carbocyclic ring moiety of 3, 4, 5, 6 or 7 ring atoms, e.g. cyclopropa, cyclobuta, cyclopenta, cyclohexa or cyclohepta, such as cyclopropa, cyclopenta, cyclohexa or cyclohepta, fused to the indane backbone structure. In another possible subgroup of the compounds of formula (I), —A— forms a fused, partially saturated monocyclic carbocyclic ring system of 5, 6 or 7 ring atoms, which contains one double bond, e.g. a fused cyclopentene or cyclohexene ring. The said fully or partially saturated carbocyclic ring system fused to the indan backbone can optionally be substituted with one to three, e.g. one or two, such as one, substituent(s) R
2
as defined above, and/or further be fused with an unsubstituted benzene ring or with a benzene ring substituted with one to three substituents R
1
as defined above.
In another possible subgroup of the compounds of formula (I), —A— forms a fused, fully or partially saturated bicyclic bridged carbocyclic ring system of 6 to 10 ring atoms, e.g. of 7 or 8 ring atoms, such as a fused bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane ring. The said bridged carbocyclic ring moiety can optionally be substituted with one to three, e.g. one or two, such as one, substituent(s) R
2
as defined above and/or further be fused with an unsubstituted benzene ring or with a benzene ring substituted with one to three substituents R
1
as defined above.
The following subgroups (1) to (6) of compounds of formula I taken alone or in any combination with each other are possible,
(1) m is 0 or 1; e.g. 0
(2) m is 1 and R
2
is halogen, OH, ═O, NH
2
, ═CH
2
, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxy, halo-(C
1-6
)alkyl, OH—(C
1-6
)alkyl, NH
2
—(C
1-6
)alkyl or mono- or di(C
1-6
)alkylamino; e.g. OH, ═O, ═CH
2
, (C
1-6
)alkyl, or (C
1-6
)alkoxy; e.g. OH, ═O, ═CH
2
or (C
1-6
)alkyl; such as (C
1-6
)alkyl or ═CH
2
;
(3) t is 0 or 1; e.g. 0;
(4) t is 1 and R
1
is selected from halogen, OH, NH
2
, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl, (C
1-6
)alkoxy, halo-(C
1-6
)alkyl, OH—(C
1-6
)alkyl, mono- or di(C
1-6
)alkylamino or OH—(C
1-6
)alkoxy(C
1-6
)alkoxy; e.g. halogen, OH, (C
1-6
)alkyl, (C
1-6
)alkoxy and OH—(C
1-6
)alkoxy(C
1-6
)alkoxy; such as halogen, e.g. F, OH, (C
1-6
)alkoxy and OH—(C
1-6
)alkoxy(C
1-6
)alkoxy;
(5) R
3
is selected from H, OH, ═O, ═CH
2
, (C
1-6
)alkyl, (C
2-6
)alkenyl and (C
1-6
)alkoxy; e.g. H, OH, ═O, ═CH
2
and (C
1-6
)alkyl; such as H, OH and ═O; e.g. H; and
(6) the —A— ring fused to the indan ring is further fused with an unsubstituted benzene ring or a benzene ring substituted with one to three, e.g. one, substituents R
1
as defined above, e.g. under (4).
A possible subgroup of the compounds of formula I are compounds of formula Ia
wherein R
1
, R
2
, R
3
, m and t are as defined above and n is 1,2,3, 4 or 5.
In a subgroup of compounds Ia, m is 0. In another subgroup of compounds Ia, m is 1 and R
2
is selected from halogen, OH, ═O, ═CH
2
, (C
1-6
)alkyl and (C
1-6
)alkoxy; e.g. OH, ═O, ═CH
2
and (C
1-6
)alkyl; such as (C
1-6
)alkyl and ═CH
2
. In a further subgroup of compounds Ia, t is 0. In another subgroup of compounds Ia, t is 1 and R
1
is selected from halogen, OH, (C
1-6
)alkyl, (C
1-6
)alkoxy and OH—(C
1-6
)alkoxy(C
1-6
)alkoxy; such as halogen, OH, (C
1-6
)alkoxy and OH—(C
1-6
)alkoxy(C
1-6
)alkoxy; such as halogen, e.g. F, OH and (C
1-6
)alkoxy. In a subgroup of compounds Ia, R
3
is selected from H, OH, ═O, (C
1-6
)alkyl, (C
2-6
)alkenyl and (C
1-6
)alkoxy; e.g. H, OH, ═O and (C
1-6
)alkyl; such as H, OH and ═O; e.g. H. In one embodiment of the compounds of formula Ia, the carbocyclic ring fused to the indan ring is further fused with an unsubstituted or substituted benzene ring. The substituted benzene ring bears one to three, e.g. one, substituent(s) R
1
as defined above; e.g. each R
1
is independently halogen, OH, (C
1-6
)alkyl, (C
1-6
)alkoxy or OH—(C
1-6
)alkoxy(C
1-6
)alkoxy; such as halogen, OH, (C
1-6
)alkoxy and OH—(C
1-6
)alkoxy(C
1-6
)alkoxy; such as halogen, e.g. F, OH or (C
1-6
)alkoxy.
Another possible subgroup of the compounds of formula I are compounds of formula Ib
wherein R
1
, R
2
, R
3
and t are as defined above; m is 0, 1 or 2; t′ is 0, 1, 2 or 3; p is 0, 1, 2 or 3; and v is0, 1, 2 or 3, with the proviso that p+v is 1, 2 or 3.
In a subgroup of compounds Ib, (a) p is 0 and v is 1, 2 or 3, or (b) v is 0 and p is 1, 2 or 3.
A subgroup of compounds Ib are compounds of formula Ib′.
wherein R
1
, R
2
, R
3
and t are as defined above; m is 0, 1 or 2; t′ is 0, 1, 2 or 3; and v is 1, 2 or 3.
In a subgroup of compounds of formula Ib, m is 0; or m is 1 and R
2
is halogen, e.g. F or Cl, or (C
1-6
)alkyl; e.g. (C
1-6
)alkyl. Preferably, t and/or t′ is 0 or 1, e.g. 0. R
3
is e.g. H. In one embodiment of the compounds Ib, v is 1 or 2.
The compounds of formula I and the subgro

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