Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-17
2002-07-16
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S248000, C514S249000, C514S257000, C514S300000, C544S184000, C544S236000, C544S281000, C544S127000, C544S061000, C544S350000, C546S121000
Reexamination Certificate
active
06420365
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain imidazopyridines and related azacyclic 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.
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. The effects of bradykinin and kallidin are mediated by specific seven transmembrane G-protein coupled receptors.
The existence of two bradykinin receptor subtypes has 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 followed by the cloning and pharmacological characterization of a human BK-2 receptor. The expression and cloning of a human bradykinin (B
1
) receptor has also been described.
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 Central Nervous System (CNS).
The B
2
receptor is expressed constitutively in a variety of tissues and accounts for the majority of the acute pharmacological effects of bradykinin. The B
1
receptor is inducibly expressed and appears to act predominantly in pathophysiological conditions. 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. Bradykinin and the related peptide kallidin have been implicated in a number of disease conditions, including but not limited to pain, rhinitis, anaphylaxis, inflammatory bowel disease, vascular permeability, algesia, vasodilataion, inflammatory response, hypotension associated with sepsis, bronchopulmonary disorders including asthma, 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. Therefore agonists of the BK-2 receptor may be useful in the treatment of Type II diabetes. An increased permeability of the blood-brain barrier due to bradykinin has also been reported. Thus, agonists of the BK-2 receptor may 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 have 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.
DESCRIPTION OF THE RELATED ART
Various compounds have been prepared as modulators of BK-2 receptors. The following disclose non-peptidic compounds that modulate Bradykinin B
2
receptors: EP-622361-A1, WO 98/42672, WO 97/41104, WO 97/28153, WO 96/13485, EP-596406-A1, EP-835659-A1, EP-808-838-A1, EP-796-848-A1, WO 98/03503, WO 97/24349, U.S. Pat. No. 5,438,064, U.S. Pat. No. 5,216,165, U.S. Pat. No. 5,212,182, WO 97/30048, EP 790239-A1, U.S. Pat. No. 5,510,380, U.S. Pat. No. 5,817,756.
The compounds most closely related structurally to the present invention are a series of imidazopyridine ureas described in JP 95-350957 as cholesterol acyltransferase inhibitors. None of the compounds from JP 95-350957 are described as bradykinin antagonists.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I (shown below) and pharmaceutical compositions comprising compounds of Formula I. Such compounds exhibit high selectivity for bradykinin B
2
receptors. 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 an 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.
A broad aspect of the invention is directed to compounds of Formula I:
or the pharmaceutically acceptable non-toxic salts thereof wherein:
represents a nitrogen-containing ring system, in which not more than two of A, B, C, or D represent nitrogen and remaining ring members are carbon, and which nitrogen-containing ring system is optionally substituted with up to four substituents independently selected from:
(i) hydroxyl, halogen, trifluoromethyl, C
1
-C
6
alkyl, trifluoromethoxy, C
1
-C
6
alkoxy, aminomethyl, mono or di(C
1
-C
6
)alkylamino, mono or dialkylaminomethyl (wherein each alkyl is independently lower C
1
-C
6
alkyl),
(ii) C
1
-C
6
alkoxyNR
7
R
8
, NR
7
R
8
, NR
7
COR
8
, CONR
7
R
8
, wherein R
7
and R
8
are same or different and represent hydrogen, or straight or branched chain lower alkyl, or R
7
and R
8
are joined together to form a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C
1
-C
6
alkyl, amino, mono or di(C
1
-C
6
)alkylamino, or C
1
-C
6
alkoxy, and
(iii) O(CH
2
)
n
CO
2
R
A
(where n=1,2,3, or 4), COR
A
, and CO
2
R
A
wherein R
A
represents hydrogen, or straight or branched chain lower alkyl;
R
1
is arylalkyl, heteroarylalkyl, or allyl each of which is optionally substituted directly or through a O(CH
2
)
n
linker (where n=1,2, 3 or 4) with up to three substituents independently selected from:
(i) halogen (with the proviso that R
1
may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C
1
-C
6
alkyl, amino, C
1
-C
6
alkoxy, aminomethyl, mono or di(C
1
-C
6
)alkylamino, mono or dialkylaminomethyl (wherein each alkyl is independently lower C
1
-C
6
alkyl),
(ii) C
1
-C
6
alkoxyNR
7′
R
8′
, NR
7′
R
8′
, NR
7′
COR
8′
, CONR
7′
R
8′
, wherein R
7′
and R
8′
are the same or different and represent hydrogen, or straight or branched ch
Hodgetts Kevin
Hutchison Alan
Lew Richard
Maynard George D.
Peterson John M.
Dentz Bernard
Fidel Seth A.
Horvath Leslie-Anne
Neurogen Corporation
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