Aryl and hetroaryl fused aminoalkyl-imidazole derivatives:...

Details Aryl and hetroaryl fused aminoalkyl-imidazole derivatives:... Aryl and hetroaryl fused aminoalkyl-imidazole derivatives:...

2000-03-31

2002-03-19

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S139000, C544S370000, C546S118000, C546S199000, C546S273400, C548S253000, C548S306100, C548S309700

Reexamination Certificate

active

06358949

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to aryl and heteroaryl fused aminoalkylimidazole derivatives which, when appropriately substituted, are selective modulators of Bradykinin B
2
receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of central and peripheral disorders. Additionally, compounds of this invention are useful as positive controls in assays for BK-2 receptor activity and when appropriately labeled as probes for the localization of BK-2 receptors in tissue sections.
2. Background
Bradykinin (BK), a nonapeptide, and the closely related decapeptide kallidin (Lys-BK), are produced by proteolytic cleavage of high molecular weight kininogen by plasma kallikreins (Bhoola et al.,
Pharmacol. Rev
. 1992, 1-80; Regoli et al.
Pharmacol. Rev
. 1980 1-46; Bathon & Proud,
Ann. Rev. Pharmac. Toxic
. 1991, 129-162). The effects of bradykinin and kallidin are mediated by specific seven transmembrane G-proteirn coupled receptors.
The existence of two bradykinin receptor subtypes was initially proposed by Regoli and Barabe (
Pharmacol. Rev
., 1980, 1-46) and this hypothesis had been unequivocally confirmed within the last six years. The expression and cloning of a rat bradykinin receptor, now known to be a BK-2 receptor, was first reported by McEachern et al. (
PNAS
1991, 88(17):7724-7728). Hess, et al. (
Biochem Biophys. Res. Commun
. 1992, 260-268) reported the cloning and pharmacological characterization of a human BK-2 receptor. Menke, et al. (
J. Biol. Chem
. 1994, 21583-21586) describes the expression and cloning of a human bradykinin (B
1
) receptor.
Both BK and kallidin activate the B
2
receptor while only kallidin is active at the B
1
receptor. However, both compounds are rapidly cleaved to produce B
1
receptor agonists, and then further degraded by kinases to produce inactive peptides. The instability of BK and kallidin suggests that these peptides act. locally. Both receptors are expressed in a number of peripheral tissues as well as in the CNS.
The B
2
receptor is expressed constitutively in a variety of: tissues (Regoli et al.,
Eur. J. Pharmacol
., 1981, 105-115) and accounts for the majority of the acute pharmacological effects of bradykinin. The B
1
receptor is inducibly expressed (Regoli et al.,
Eur. J. Pharmacol
., 1981, 105-115; Deblois et al.,
Immunopharmacology
, 1989, 187-98; Marceau,
Immunopharmacology
, 1995, 1-26.) and appears to act predominantly in, pathophysiological conditions (Dray and Perkins,
J. Neurophysiol
., 1993, 256-272). The BK-1 receptor has been especially implicated in persistent hyperalgesia and chronic inflammation.
Bradykinin is an effector of a number of inflammatory responses including bronchoconstriction, plasma extravasation, release of prostaglandins/leukotrienes, smooth muscle contraction/relaxation and nociception (Burch et al.,
Med. Res. Rev
. 1990, 237-269). Bradykinin and the related peptide kallidin have been implicated in a number of disease conditions, including but not limited to pain (Whalley et al.,
Naunyn. Schmiedeberg's Arch. Pharmc
., 1987, 652-655), rhinitis, anaphylaxis, inflammatory bowel disease, vascular permeability (Schachter et al.,
Br. J. Pharmac
., 1987, 851-855; Whalley et al.,
Naunyn Schmiedeberg's Arch. Pharmc
., 1987, 430-433), algesia, vasodilataion, inflammatory response (Burch & De Haas,
Naunyn Schmiedeberg's Arch. Pharmc.
1990, 189-193), hypotension associated with sepsis (Sharma et al.,
Agents Actions
, 1992, 258-269), bronchopulmonary disorders including asthma (Jin et al.,
Br. J. Pharmac
., 1989, 598-602), and increased cell proliferation. Antagonists of the BK-2 receptor are useful in treating these conditions. Additionally bradykinin has been implicated in increased glucose uptake, and decreased blood glucose concentration (Henriksen et al.,
Diabetes
, 1996, S125-S128; Yang et al.,
J Pharmacol. Exp. Ther
., 1997, 1247-1252). Therefore agonists of the BK-2 receptor may be useful in the treatment of Type II diabetes. Unterberg et al. (
J Cereb. Blood Flow Metab
., 1984, 574-585) report an increased permeability of the blood-brain barrier due to bradykinin. Thus, agonists of the BK-2 receptor could also be used to increase the brain levels of pharmaceutical compounds used to treat central nervous system disorders when administered with these compounds. Therefore, compounds that modulate the bradykinin B
2
(BK-2) receptor as agonists or antagonists would have considerable therapeutic benefit.
A number of tissues and cultured cell lines has been assessed for the presence of bradykinin receptors using radiolabeled bradykinin or a radiolabeled bradykinin analogue as a probe (See Hall,
Gen. Pharma
., 1997, 28: 1-6, for a compilation of such studies.). Although bradykinin and its analogues exhibit high affinity for bradykinin receptors there are some difficulties in using these ligands as receptor localization probes. Bradykinin binds to both BK-1 and BK-2 receptors and therefore cannot be used to distinguish receptor subtypes. Also bradykinin and many of its peptide analogues are susceptible to rapid degradation by kininases, leading to experimental difficulties. Nonpeptidic ligands are not susceptible to kininase activity. Therefore, small molecules that bind with high affinity and high selectivity to BK-2 receptors are especially desirable tools for BK-2 localization studies.
SUMMARY OF THE INVENTION
This invention provides compounds of Formula I (shown below) and pharmaceutical compositions comprising compounds of Formula I. Preferred compounds of the invention exhibit high selectivity for G-coupled protein receptors, especially bradykinin B
2
receptors. Preferred compounds of Formula I also bind with high affinity to these receptors.
The invention further provides methods of treating patients suffering from certain inflammatory disorders and other conditions mediated by bradykinin. The invention also provides methods of treating patients (humans and non-humans) suffering from conditions in which agonism of the BK-2 receptor may prove beneficial. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with art effective amount of a compound of the invention is contemplated by the invention.
In a separate aspect, the invention provides methods of using compounds of this invention as positive controls in assays for BK-2 receptor activity and using appropriately labeled compounds of the invention as probes for the localization of BK-2 receptors in tissue sections.
Accordingly, in one aspect, the invention is directed to compounds of Formula I:
wherein:
R
1
is not 3-fluorobenzyl and represents
(i) (C
2
-C
6
)alkenyl; or
(ii) R
1
represents aryl(C
1
-C
6
)alkyl or heteroaryl(C
1
-C
6
)alkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, amino, mono- or di(C
1
-C
6
)alkylamino, amino(C
1
-C
6
)alkyl, mono- or di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, mono- or di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkoxy, or
(iii) OR
7
, O(CH
2
)
n
C(O)R
7
, O(CH
2
)
n
NR
7
R
8
, O(CH
2
)
n
CO
2
R
7
, NR
7
COR
8
, COR
7
, CONR
7
R
8
or CO
2
R
7
where
n=1, 2, 3, or 4 and
R
7
and R
8
are the same or different and represent hydrogen, SO
2
Me, or (C
1
-C
6
)alkyl; or
R
7
and R
8
together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members in the ring are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C
1
-C
6
)alkyl;
R
2
represents
hydrogen, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, amino(C
1
-C
6
)alkyl, mono- or di(C
1
-C
6
)alkylamino(C
1
-C
6
), mono- or di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkoxy; or
OR
7
, O(CH
2
)
n
C(O)R
7
, O(CH
2
)
n
NR
7
R
8
, O(C

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