Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-06
2003-10-28
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S231500, C514S258100, C514S326000, C548S527000, C548S517000, C546S187000, C546S212000, C546S268100, C546S269700, C546S281700, C544S106000, C544S147000, C544S152000
Reexamination Certificate
active
06638967
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to bicyclic derivatives, their synthesis and their use, for example, for the treatment of disorders and conditions mediated by the histamine receptor.
BACKGROUND OF THE INVENTION
Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance. Histamine exerts a physiological effect via multiple distinct G-protein coupled receptors. It plays a role in immediate hypersensitivity reactions and is released from mast cells following antigen IgE antibody interaction. The actions of released histamine on the vasculature and smooth muscle system account for the symptoms of the allergic response. These actions occur at the H
1
receptor (Ash, A. S. F. and Schild, H. O.,
Br. J. Pharmacol.,
1966, 27, 427) and are blocked by the classical antihistamines (e.g. diphenhydramine). Histamine is also an important regulator of gastric acid secretion through its action on parietal cells. These effects of histamine are mediated via the H
2
receptor (Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R. and Parsons, E. M.,
Nature,
1972, 236, 385) and are blocked by H
2
receptor antagonists (e.g. cimetidine). The third histamine receptor—H
3
—was first described as a presynaptic autoreceptor in the central nervous system (CNS) (Arrang, J.-M., Garbarg, M., and Schwartz, J.-C.,
Nature
1983, 302, 832) controlling the synthesis and release of histamine. Recent evidence has emerged showing that the H
3
receptors are also located presynaptically as heteroreceptors on serotonergic, noradrenergic, dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acid containing) neurons. These H
3
receptors have also recently been identified in peripheral tissues such as vascular smooth muscle. Consequently there are many potential therapeutic applications for histamine H
3
agonists, antagonists, and inverse agonists. (See: “
The Histamine H
3
Receptor
-
A Target for New Drugs
”, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998; Morisset et al.,
Nature,
2000, 408, 860-864.) A fourth histamine receptor—H
4
—was recently described by Oda et al., (J. Biol. Chem., 2000, 275, 36781-36786).
The potential use of histamine H
3
agonists in sleep/wake and arousal/vigilance disorders is suggested based on animal studies (Lin et al,
Br. Res.,
1990, 523, 325; Monti et al
Eur. J. Pharmacol.,
1991, 205, 283). Their use in the treatment of migraine has also been suggested (McLeod et al
Abstr. Society Neuroscience,
1996, 22, 2010) based on their ability to inhibit neurogenic inflammation. Other applications could be a protective role in myocardial ischemia and hypertension where blockade of norepinephrine release is beneficial (Imamura et al
J. Pharmacol. Expt. Ther.,
1994, 271,1259). It has been suggested that histamine H
3
agonists may be beneficial in asthma due to their ability to reduce non-adrenergic non-cholinergic (NANC) neurotransmission in airways and to reduce microvascular leakage (Ichinose et al
Eur. J. Pharmacol.,
1989,174, 49).
Several indications for histamine H
3
antagonists and inverse agonists have similarly been proposed based on animal pharmacology experiments with known histamine H
3
antagonists (e.g. thioperamide). These include dementia, Alzheimer's disease (Panula et al
Abstr. Society Neuroscience,
1995, 21,1977), epilepsy (Yokoyama et al
Eur. J. Pharmacol.,
1993, 234,129) narcolepsy, eating disorders (Machidori et al
Brain Research
1992, 590,180), motion sickness, vertigo, attention deficit hyperactivity disorders (ADHD), learning and memory (Barnes et al
Abstr. Society Neuroscience,
1993,19,1813), schizophrenia (Schlicker et al
Naunyn
-
Schmiedeberg's Arch. Pharmacol.,
1996, 353, 290-294); (also see; Stark et al
Drugs Future,
1996, 21, 507 and Leurs et al
Progress in Drug Research,
1995, 45, 107 and references cited therein). Histamine H
3
antagonists, alone or in combination with a histamine H
1
antagonist, are reported to be useful for the treatment of upper airway allergic response (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479). Recently, a histamine H
3
antagonist (GT-2331) was identified and is being developed by Gliatech Inc. (Gliatech Inc. Press Release Nov. 5,1998;
Bioworld Today,
Mar. 2,1999) for the treatment of CNS disorders.
As noted, the prior art related to histamine H
3
ligands has been comprehensively reviewed (“
The Histamine H
3
Receptor
-
A Target for New Drugs
”, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998). Within this reference the medicinal chemistry of histamine H
3
agonists and antagonists was reviewed (see Krause et al and Phillips et al respectively). The importance of an imidazole moiety containing only a single substitution in the 4 position was noted together with the deleterious effects of additional substitution on activity. Particularly methylation of the imidazole ring at any of the remaining unsubstituted positions was reported to strongly decrease activity. Additional publications support the hypothesis that an imidazole function is essential for high affinity histamine H
3
receptor ligands (See, Ali et al
J. Med. Chem.,
1999, 42, 903 and Stark et al,
Drugs Future,
1996, 21, 507 and references cited therein). However many imidazole containing compounds are substrates for histamine methyl transferase, the major histamine metabolizing enzyme in humans, which leads to shortened half lives and lower bioavailability (See, Rouleau et al
J. Pharmacol. Exp. Ther.
1997, 281,1085). In addition, imidazole containing drugs, via their interaction with the cytochrome P450 monooxygenase system, can result in unfavorable biotransformations due to enzyme induction or enzyme inhibition. (Kapetanovic et al
Drug Metab. Dispos.
1984,12, 560; Sheets et al
Drug Metab. Dispos.
1984,12, 603; Back, et al
Br. J. Pharmacol.
1985, 85,121; Lavrijsen et al
Biochem. Pharmacol.
1986, 35, 1867
; Drug Saf.,
1998, 18, 83). The poor blood brain barrier penetration of earlier histamine H
3
receptor ligands may also be associated with the imidazole fragment (Ganellin et al
Arch. Pharm.
(
Weinheim,Ger.
) 1998, 331, 395).
More recently, several publications have described histamine H
3
ligands that do not contain an imidazole moiety. For example; Ganellin et al
Arch. Pharm.
(
Weinheim,Ger.
) 1998, 331, 395; Walczynski et al
Arch. Pharm.
(
Weinheim,Ger.
) 1999, 332, 389; Walczynski et al Farmaco 1999, 684; Linney et al
J. Med. Chem.
2000, 2362; Tozer and Kalindjian
Exp. Opin. Ther. Patents
2000,10,1045-1055; U.S. Pat. No. 5,352,707; PCT Application W099/42458, Aug. 26,1999; and European Patent Application 0978512, Feb. 9, 2000.
The compounds of the present invention do not contain the imidazole moiety, and its inherent liabilities, and maintain potency at the human H
3
receptor. Thus in the present invention receptor binding was determined using the human histamine H
3
receptor (See Lovenberg et al
Mol. Pharmacol.
1999, 1107). Screening using the human receptor is particularly important for the identification of new therapies for the treatment of human disease. Conventional binding assays for example are determined using rat synaptosomes (Garbarg et al
J. Pharmacol. Exp. Ther.
1992, 263, 304), rat cortical membranes (West et al
Mol. Pharmacol.
1990, 610), and guinea pig brain (Korte et al Biochem.
Biophys. Res. Commun.
1990, 978). Only limited studies have been performed previously using human tissue but these allude to significant differences in the pharmacology of rodent and primate receptors (West et al
Eur. J. Pharmacol.
1999, 233).
We now describe a series of bicyclic derivatives with the ability to modulate the activity of the histamine receptor, specifically the H
3
receptor, without the inherent problems associated with the presence of an imidazolyl moiety.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of formula (I):
wherein each of W
1
and W
2
is H;
X
1
is selected from G
a
, R
a
G
a
, L
a
G
a
, and R
a
L
a
G
a
;
X
2
is selected from G
b
, R
b
G
b
, L
b
G
b
, and R
b
L
Bogenstaetter Michael
Chai Wenying
Kwok Annette K.
Desai Rita
Ortho-McNeil Phamraceutical, Inc.
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