Substituted imidazole derivatives and their use as histamine...

Details Substituted imidazole derivatives and their use as histamine... Substituted imidazole derivatives and their use as histamine...

2000-03-13

2002-06-18

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S339500, C548S340100

Reexamination Certificate

active

06407132

ABSTRACT:

This application is a 371 of PCT/GB98/02063 filed Jul. 14, 1998.
This invention relates to compounds which bind to histamine H
3
receptors, and to methods of making such compounds.
Histamine is well known as a mediator in certain hypersensitive reactions of the body, such as allergic rashes, hayfever and asthma. These conditions are now commonly treated with potent antagonists of histamine, so-called “antihistamines”.
In the 1940s, it was noted that some physiological effects of histamine, such as increased gastric acid secretion and cardiac stimulation, were not blocked by the antihistamines which were then available. This led to the proposal that histamine receptors exist in at least two distinct types, referred to as H
1
and H
2
receptors. Subsequently, H
2
antagonists (such as cimetidine, ranitidine and famotidine) were identified and they have become important in the treatment of gastric ulcers.
In the early 1980s, it was established that histamine also has a role as a neurotransmitter in the central nervous system. Arrang et al.,
Nature
302, 832 to 837 (1983), proposed the existence of a third histamine receptor subtype (H
3
) located presynaptically on histaminergic nerve endings. Arrang et al. postulated that the H
3
receptor is involved in inhibiting the synthesis and release of histamine in a negative feedback mechanism The existence of the H
3
receptor was subsequently confirmed by the development of selective H
3
agonists and antagonists (Arrang et al.,
Nature
327, 117 to 123 (1987)). The H
3
receptor has subsequently been shown to regulate the release of other neurotransmitters both in the central nervous system and in peripheral organs, in particular in the lungs and GI tract. In addition, H
3
receptors are reported to regulate the release of histamine from mast cells and enterochromaffinike cells.
A need exists for potent and selective H
3
ligands (both agonists and antagonists) as tools in the study of the role of histamine as a neurotransmitter, and in its roles as a neuro-, endo- and paracrine hormone. It has also been anticipated that H
3
ligands will have therapeutic utility for a number of indications including use as sedatives, sleep regulators, anticonvulsants, regulators of hypothalamo-hypophyseal secretion, antidepressants and modulators of cerebral circulation, and in the treatment of asthma and irritable bowel syndrome.
A number of imidazole derivatives have been proposed in the patent literature as H
3
ligands. Representative are the disclosures of EP-A-0197840, EP-A-0214058, EP-A-0458661, EP-A-0494010, EP-A-0531219, WO91/17146, WO92/15567, WO93/01812, WO93/12093, WO93/12107, WO93/12108, WO93/14070), WO93/20061, WO94/17058, WO95/06037, WO95/11894, WO95/14007, U.S. Pat. No. 4,988,689 and U.S. Pat. No. 5,217,986.
According to the present invention, there is provided a compound of the formula
wherein
R
1
is selected from C
1
to C
6
alkyl, C
1
to C
6
alkoxy, C
1
to C
6
alkylthio, carboxy, carboxy(C
1
to C
6
)alkyl, formyl, C
1
to C
6
alklycarbonyl, C
1
to C
6
−
alkylcarbonylalkoxy, nitro, trihalomethyl, hydroxy, amino, C
1
to C
6
alkylamino, di(C
1
to C
6
alkyl)amino, aryl, C
1
to C
6
alkylaryl, halo, sulfamoyl and cyano;
R
2
represents a bond or C
1
to C
5
(preferably C
1
to C
3
) hydrocarbylene;
R
3
is selected from the groups recited above for R
1
,
R
4
represents a bond or C
1
to C
5
(preferably C
1
to C
3
) hydrocarbylene;
R
5
is hydrogen, C
1
to C
3
alkyl, or R
8
—O—(C
1
to C
3
)alkyl (wherein R
8
is hydrogen or C
1
to C
3
alkyl), aryl, aryl(C
1
to C
3
)alkyl or heterocyclic(C
1
to C
3
)alkyl;
R
6
represents a bond or —NR
9
—, wherein R
9
is any of the groups recited above for R
5
;
R
7
is H or C
1
to C
15
hydrocarbyl (in which one or more hydrogen atoms may be replaced by halogen, and up to three carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R
7
does not contain an —O—O-group),
a is from 0 to 2 (preferably 0); and
b is from 0 to 3 (preferably 0);
and pharmaceutically acceptable salts thereof
R
5
is preferably hydrogen, C
1
to C
3
alkyl, or R
8
—O—(C
1
to C
3
)alkyl (wherein R
8
is hydrogen or C
1
to C
3
alkyl).
R
9
is preferably hydrogen, C
1
to C
3
alkyl, or R
8
—O—(C
1
to C
3
)alkyl (wherein R
8
is hydrogen or C
1
to C
3
alkyl).
R
7
is preferably hydrogen, cycloalkyl(C
1
to C
3
) alkyl, aryl or aryl(C
1
to C
3
)alkyl. Particularly preferred are compounds in which R
7
is phenyl, phenyl(C
1
to C
3
)alkyl, naphthyl or naphthyl(C
1
to C
3
)alkyl, optionally substituted by C
1
to C
6
alkyl, C
1
to C
6
alkoxy, C
1
to C
6
alkylthio, carboxy, carboxy(C
1
to C
6
)alkyl, formyl, C
1
to C
6
alkylcarbonyl, C
1
to C
6
alkylcarbonylalkoxy, nitro, trihalomethyl, hydroxy, amino, C
1
to C
6
alkylamino, di(C
1
to C
6
alkyl)amino, halo, sulfamoyl and cyano.
R
2
is preferably a bond or C
1
to C
3
hydrocarbylene.
R
4
is also preferably a bond or C
1
to C
3
hydrocarbylene.
The invention also comprehends derivative compounds (“pro-drugs”) which are degraded in vivo to yield the species of formula (1). Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded. Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of pro-drugs may be found in Stella, V. J. et al., “Prodrugs”,
Drug Delivery Systems
, pp. 112-176 (1985), and
Drugs
, 29, pp.455-473 (1985).
Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (I) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form —COOR
10
, wherein R
10
is C
1
to C
5
alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following:
Amidated acid groups include groups of the formula —CONR
11
R
12
, wherein R
11
is H, C
1
to C
5
alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R
12
is —OH or one of the groups just recited for R
11
.
Compounds of formula (I) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution.
Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, and zinc, and salts with organic bases. Suitable organic bases include
N
-methyl-D-glucamine, benzathine, diolamine, olamine, procaine and tromethamine.
Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.
The compounds of the invention may exist in various enantiomeric, diastereomeric and tautomeric forms. It will be understood that the invention comprehends the different enantiomers, diastereomers and tautomers in isolation from each other, as well as mixtures of enantiomers, diastereomers and tautomers.
The term “hydrocarbyl”, as used herein, refers to monovalent groups consisting of carbon and hydrogen. Hydrocarbyl groups thus include alkyl, alkenyl, and alkynyl groups (in both straight and branched chain forms), cycloalkyl (including polycycloalkyl), cycloalkenyl, and aryl groups, and combinations of the foregoing, such as alkylaryl, alk

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