Substituted imidazoles as dual histamine H1 and H3 agonists...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S333000, C514S396000, C514S399000, C514S400000, C546S256000, C546S272700, C546S275100, C548S338100, C548S300100

Reexamination Certificate

active

06518287

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel substituted imidazole compounds having valuable pharmacological properties, especially against inflammatory diseases and allergic conditions. Compounds of this invention are antagonists of the histamine receptors. Some are antagonists of the histamine-H
1
receptors. Some are antagonists of the histamine-H
3
receptors. Some are antagonists of both the H
1
and H
3
receptors, in other words dual H
1
and H
3
receptor antagonists.
BACKGROUND OF THE INVENTION
The histamine receptors, H
1
, H
2
and H
3
are well-identified forms. The H
1
receptors are those that mediate the response antagonized by conventional antihistamines. H
1
receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. A well known antagonist of H
1
receptors is loratadine, commercially available under the tradename CLARITIN® from Schering-Plough Corporation, Madison, N.J. Through H
2
receptor-mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.
H
3
receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H
3
receptor activation by histamine attenuates nonepinephrine outflow to resistance and capacitance vessels, causing vasodilatation.
U.S. Pat. No. 4,767,778 (Arrang et al.) discloses certain imidazoles that behave as agonists of the H
3
receptors in rat brain. European Patent Application No. 0 420 396 A2 (Smith Kline & French Laboratories Limited) and Howson et al. (
Bioorg
. &
Med. Chem. Letters
, (1992), Vol. 2 No.1, pages 77-78) describe imidazole derivatives having an amidine group as H
3
agonists. Van der Groot et al. (
Eur. J. Med. Chem
. (1992) Vol. 27, pages 511-517) describe isothiourea analogs of histamine as potent agonists or antagonists of the histamine-H
3
receptor, and these isothiourea analogs of histamine overlap in part with those of the two references cited above. Clapham et al.. [“Ability of Histamine-H
3
Receptor Antagonists to Improve Cognition and to Increase Acetylcholine Release in vivo in the Rat”,
British Assn. for Psychopharmacology
, Jul. 25-28 (1993), reported in
J. Psychopharmacol
. (Abstr. Book), A17] describe the ability of histamine-H
3
receptor antagonists to improve cognition and to increase release of acetylcholine in vivo in the rat. Clapham et al.. [“Ability of the selective Histamine-H
3
Receptor Antagonist Thioperamide to improve Short-term Memory and Reversal Learning in the Rat”,
Brit. J. Pharm. Suppl.,
1993, 110, Abstract 65P] present results showing that thioperamide can improve short-term memory and reversal learning in the rat and implicate the involvement of H
3
receptors in the modulation of cognitive function. Yokoyama et al.. [“Effect of Thioperamide, a Histamine-H
3
Receptor Antagonist, on Electrically Induced Convulsions in Mice”,
Eur. J. Pharmacol
., (1993), Vol. 234, pages 129-133] report how thioperamide decreased the duration of each phase of convulsion and raised the electroconvulsive threshold, and go on to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures. International Patent Publication No. WO 9301812-A1 (SmithKline Beecham PLC) describes the use of S-[3-(4(5)-imidazolyl)propyl]isothiourea as a histamine-H
3
antagonist, especially for treating cognitive disorders, e.g. Alzheimer's disease and age-related memory impairment. Schlicker et al. [“Novel Histamine-H
3
Receptor Antagonists: Affinities in an H
3
Receptor Binding Assay and Potencies in Two Functional H
3
Receptor Models”,
British J. Pharmacol
., (1994), Vol.112,1043-1048] describe a number of imidazolylalkyl compounds wherein the imidazolylalkyl group is bonded to a guanidine group, an ester group, an amide group, a thioamide group and a urea group, and compared these to thioperamide. Leurs et al. [“The Histamine-H
3
-receptor: A Target for Developing New Drugs”,
Progr. Drug Res
. (1992), Vol. 39, pages 127-165] and Lipp et al. [“Pharmacochemistry of H
3
-receptors” in
The Histamine Receptor
, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pages 57-72] review a variety of synthetic H
3
receptor antagonists, and Lipp et al. (ibid. ) have proposed the necessary structural requirements for an H
3
receptor antagonist.
WO 95/14007 claims H
3
receptor antagonists of the formula
wherein A, m, n, R
1
and R
2
are defined therein. The compounds are disclosed as being useful for treating various disorders, in particular such caused by allergy-induced responses.
WO 93/12093 discloses imidazolylmethyl piperazines and diazepines as H
3
antagonists. U.S. patent application, Ser. No. 08/965,754, filed Nov. 7, 1997, discloses imidazolylalkyl substituted heterocyclic ring compounds as H
3
receptor antagonists. U.S. patent application, Ser. No. 08/966,344, filed Nov. 7, 1997, discloses phenylalkylimidazoles as H
3
receptor antagonists.
WO 96/29315 (PCT/FR96/00432) discloses certain N-imidazolylalkyl compounds containing phenyl moieties attached.
Also disclosing H
3
receptor antagonists are: H. Stark et al,
Eur. J. of Pharmaceutical Sciences
(1995) 3, 95-104; H. Stark et al,
J. Med. Chem
., (1996) 39, 1157-1163; H. Stark et al,
Arch Pharm. Pharm. Med. Chem
., (1998) 331, 211-218; and A. Sasse et al,
Bioorganic
&
Medicinal Chem
., (2000) 8, 1139-1149.
Reference is also made to J. R. Bagley et al..
Journal of Medicinal Chemistry
, (1991), Vol. 34, 827-841, which discloses, among others, N-(imidazolylalkyl) substituted cyclic amine compounds useful as analgesics such as the amine compound with the formula:
Pending U.S. patent application, Ser. No. 09/173,642, filed Oct. 16, 1998 (R. Wolin et al.), U.S. Pat. No. 6,133,291 discloses N-(imidazolylalkyl) substituted cyclic amine compounds having H
3
antagonist activity.
A. Huls et al.,
Bioorg
. &
Med.Chem. Letters,
6 (1996), 2013-2018 disclose imidazole compounds containing diphenyl ether moieties as H
3
receptor antagonists. The compounds are additionally disclosed to have H
1
receptor antagonist activity. An example compound from that publication is:
where R
1
and R
2
are defined therein.
A. Buschauer,
J. Med. Chem.,
32 (1989), 1963-1970 disclose, among others, H
2
receptor antagonists of the type:
where Ar
1
and Ar
2
may be phenyl and/or pyridyl. EPO 448,765 A1 (published Mar. 30, 1990) discloses neuropeptide-Y antagonist imidazoles of the type:
where Ar
1
and Ar
2
may be phenyl and/or pyridyl.
WO 98-58646 (assigned to Novo Nordisk A/S) discloses somatostatin SSTR4 receptor antagonist compounds of the type:
wherein m is 2-6; n is 1-3; p is 1-6; R
1
and R
2
are independently H or C1-C6 alkyl optionally substituted with halogen, amino, hydroxy, alkoxy or aryl; X is S, O, NH, NCOPh or N(CN); A is aryl optionally substituted with halogen, amino, hydroxy, nitro, C1-6 alkyl, C1-6 alkoxy, or aryl; and B and D are independently aryl optionally substituted with halogen, amino, hydroxy, C1-6 alkyl, C1-6 alkoxy, or aryl.
Compounds have been reported in the literature as having activity against both H
1
and H
2
receptors, i.e. dual antagonists against H
1
and H
2
receptors. Thus, for example, F. Schulze et al.,
European J. of Pharmaceutical Sciences,
6 (1998), 177-186 report combined H
1
/H
2
receptor antagonists. Other references in this category include F. Schulze et al.,
Arch Pharm
. (
Weinheim
), 327 (1994), 455-462; C. Wolf et al.,
Arch Pharm. Med. Chem.,
329 (1996), 87-94; and C. Wolf et al.,
European J. of Pharmaceutical Sciences,
6 (1998), 177-186. Non-imidazole histamine H
3
ligands, particularly substituted benzothiazole derivatives as H
3
antagonists and H
1
blocking activities have been reported by K. Walczynski et al.
II Farmaco,
54 (1999), 684-694.
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