Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-29
2002-12-03
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06489337
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods of using pharmaceutically-active fused heterobicyclic compounds to treat or prevent disorders and conditions mediated by the histamine H
3
receptor.
BACKGROUND
The histamine H
3
receptor is located as a presynaptic autoreceptor in the central nervous system and as a presynaptic heteroreceptor on serotonergic, noradrenergic, dopaminergic, and cholinergic neurons. The histamine H
3
receptor is also located peripherally in tissues such as vascular smooth muscle cells.
Proposed uses of histamine H
3
antagonists include the treatment or prevention of dementia, Alzheimer's disease (Panula et al.
Abstr. Society Neuroscience,
1995, 21:1977), epilepsy (Yokoyama et al.
Eur. J. Pharmacol.,
1993, 234:129), sleep/wake disorders (Lin et al,
Br. Res.,
1990, 523, 325; Monti et al.,
Eur. J. Pharmacol.,
1991, 205, 283) including narcolepsy, insomnia, and jet lag, eating disorders (Machidori et al.
Brain Research,
1992, 590:180), motion sickness, vertigo, attention deficit hyperactivity disorder, learning and memory disorders (Barnes et al.
Abstr. Society Neuroscience,
1993,19:1813), schizophrenia (Schlicker et al.
Naunyn Schmiedeberg's Arch. Pharmacol.,
1996, 353:325), and sequelae associated with post-ischemic reperfusion and hypertension (Imamura et al.,
J. Pharmacol. Expt. Ther.,
1994, 271, 1259). H
3
antagonists are also useful to treat or prevent neurogenic inflammation such as migraine (McLeod et al.,
Abstr. Society Neuroscience,
1996, 22, 2010), asthma (Ichinose et al,
Eur. J. Pharmacol.,
989, 174, 49), obesity, allergic rhinitis, substance abuse, bipolar disorders, manic disorders, and depression. Histamine H
3
antagonists alone or in combination with a histamine H
1
antagonist are believed to be useful in the treatment of upper airway allergic response or allergic rhinitis (see, e.g., U.S. Pat. Nos. 5,217,986, 5,352,707, and 5,869,479).
As noted, the prior art related to histamine H
3
ligands was comprehensively reviewed recently (“
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). Thus 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.
More recently several publications have described histamine H
3
ligands that do not contain an imidazole moiety. Examples include 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; U.S. Pat. No.5,352,707; PCT Application WO99/42458, published Aug. 26,1999; and European Patent Application 0978512, published on Feb. 9, 2000.
SUMMARY OF THE INVENTION
The invention features the use of the compounds of formula (I) for the treatment and/or prevention of diseases and conditions mediated by the histamine 3 (H
3
) receptor.
wherein
X is H or one or more of halogen, hydroxy, C
1-3
alkoxy, benzyloxy, and C
1-6
alkyl;
R is H or Ar;
R
1
is H, methyl, or Ar;
Ar is —(C═O)
n
—Ph—O—(CH
2
)
m
—N(R
2
)
2
;
R
2
is C
1-6
alkyl;
n is 0 or 1 when R is Ar or 1 when R
1
is Ar;
m is 2-6;
at least one of R and R
1
is Ar; and both of R and R
1
are not Ar;
or a pharmaceutically acceptable salt, ester, or amide thereof.
The compounds are disclosed generically in U.S. Pat. No. 4,727,145, and JP Serial Number 236427, filed on Sep. 22, 1987 and subsequently published as JP 63091391 A2. These compounds were first identified as having local anesthetic properties.
Additional features of the invention are disclosed in the following description and examples, and in the appended claims.
DETAILED DESCRIPTION
The invention features pharmaceutically active phenyl-substituted imidazopyridines and methods of making and using them. The description is organized as follows:
A. Terms
B. Compounds
C. Synthetic Methods
D. Uses
E. Synthetic Chemical Examples
F. Biological Examples
G. Other Embodiments
H. Claims
A. Terms
The following terms are defined below and by their usage throughout this disclosure.
“Alkyl” includes straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on.
“Alkoxy” includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
“halo” or “halogen” includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro.
“patient” or “subject” includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient is a human.
“composition” includes a product comprising the specified ingredients in the specified amounts as well as any product which results directly or indirectly from combinations of the specified ingredients in the specified amounts.
Concerning the various radicals in this disclosure and in the claims, two general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent).
Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Using “alkyl” as an example, “alkyl” should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, and 3-iodocyclopentyl), hydroxyalkyl, aminoalkyl, nitroalkyl, alkylalkyl, and so on.
B. Compounds
One aspect of the invention features compounds of formula (I) as described in the Summary section above.
Preferred compounds of formula (I) include those compounds wherein: (a) each X is independently selected from H and methyl; (b) R
1
is H or methyl; (c) R is Ar; (d) R
2
is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl; (e) R
2
is methyl, ethyl, propyl, isopropyl, butyl, or pentyl; (f) n is 1; (g) n is 0; (h) m is 2, 3, or 4; (i) m is 3 or 4; (j) m is 3; or (k) combinations thereof.
More preferred compounds include those wherein X is H or methyl; R is Ar; R
1
is H or methyl; m is 2, 3, or 4; and n is 0. In one aspect, there is a single X as methyl; in another aspect, there is more than one X that is methyl, a halogen, or hydroxy.
Preferred compounds include: 2-(4-dibutylaminopropoxyphenyl)imidazo[1,2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-8-methylimidazo[1,2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-6-bromoimidazo[1,2-a]-pyridine; 2-(4-dibutylaminopropoxyphenyl)-7-methylimidazo-[1,2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-3,8-dimethyl imidazo[1,2-a]pyridi
Breitenbucher J. Guy
Carruthers Nicholas I.
Li Xiaobing
Lovenberg Timothy W.
Jarvis William R. A.
Ortho-McNeil Pharmaceutical , Inc.
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