Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-18
2002-07-09
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S400000, C548S345100
Reexamination Certificate
active
06417218
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel substituted imidazoles, to methods for their preparation, to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating a histamine H3 receptor antagonistic or agonistic activity. As a result, the compounds are useful for the treatment of disorders related to the histamine H3 receptor. More particularly, the present compounds possess a histamine H3 receptor antagonistic activity and accordingly are useful for the treatment of disorders in which a histamine H3 receptor blockade is beneficial.
2. Description of the Related Art
The histamine H3 receptor is known and of current interest for the development of new medicaments (see e.g. Stark, H.; Schlicker, E.; Schunack, W.,
Drugs Fut.
1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C.,
Progress in Drug Research
1995, 45, 107-165). The histamine H3 receptor is a presynaptic autoreceptor located in both the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis and release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists.
Thus, U.S. Pat. No. 4,767,778 (corresponding to EP 214 058), EP 338 939, EP 531 219, EP 458 661, WO 91/17146, WO 92/15567, WO 96/38142 and WO 96/38141 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. However, none of these derivatives has a five or six membered carbocyclic ring optionally containing one or two double bonds directly attached to the 4-position of the imidazole ring such as is the case in the present compounds.
WO 93/12093 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. These derivatives have a six or seven membered nitrogen containing ring in the 4-position of the imidazole ring which nitrogen containing ring is attached to the imidazole ring via a methylene group. EP 197 840, EP 494 010, WO 95/11894, WO 93/20061, WO 93/12108, WO 93/12107, WO 94/17058 and WO 95106037 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. These derivatives have a five or six membered nitrogen containing ring attached to the 4-position of the imidazole ring and thus differ structurally from the present compounds which have a five or six membered carbocyclic ring optionally containing one or two double bonds in the same position.
WO 93/14070 disclose imidazole derivatives having histamine H3 antagonistic activity. These derivatives have a hydrocarbon chain optionally containing one or more heteroatoms attached to the 4-position of the imidazole ring which hydrocarbon chain may bear a cycloalkyl or cycloalkenyl group. U.S. Pat. No. 5,578,616 (corresponding to WO 95/14007) discloses phenyl-alkyl imidazoles as histamine H3 receptor antagonists. These phenyl-alkyl imidazoles differ structurally from the present compounds by having a C
1-3
-alkylene group inserted between the imidazole ring and the phenyl ring. In the present compounds, on the contrary, the imidazole ring is directly attached to a five or six membered carbocyclic ring optionally containing one or two double bonds.
WO 96/40126 discloses substituted imidazole derivatives having histamine H3 receptor agonistic activity. Some of these may have a cyclohexyl group directly attached to the 4-position of the imidazole ring. However, a nitrogen atom is always attached to the 4-position of the cyclohexyl ring.
Furthermore, WO 98/07718 and Chemical Abstracts, Volume 84, No 11, Mar. 15, 1976, 73197p disclose imidazole derivatives. However, they are not disclosed as histamine H3 receptor agonists or antagonists.
In view of the arts' interest in histamine H3 receptor agonists and antagonists, novel compounds which trigger the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of substituted imidazole compounds has a high and specific affinity to the histamine H3 receptor and possesses histamine H3 receptor antagonistic activity.
Due to their histamine H3 receptor antagonistic activity the present compounds are useful in the treatment and/or prevention of a wide range of conditions and disorders in which a blockade of the histamine H3 receptor is beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinologic system.
Definitions
In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning:
The term “C
1-6
-alkyl” as used herein represents a branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Typical C
1-6
-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
The term “C
1-6
-alkoxy” as used herein, alone or in combination, refers to the radical —O—
1-6
-alkyl where C
1-6
-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term “C
1-6
-alkylsulfonyl” as used herein, alone or in combination, refers to the radical —S(═O)
2
—C
1-6
-alkyl where C
1-6
-alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl and the like.
The term “C
3-8
-cycloalkyl” as used herein represents a carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term “aryl” as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1-(1,2,3,4-tetrahydronaphthyl) and 2-(1,2,3,4-tetrahydronaphthyl).
The term “arylsulfonyl” as used herein refers to the radical —S(═O)
2
-aryl where aryl is as defined above. Non-limiting examples are phenylsulfonyl, naphthylsulfonyl, phenanthrenylsulfonyl, fluorenylsulfonyl, indenylsulfonyl and the like.
The term “heteroaryl” as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, inda
Andersen Knud Erik
Dorwald Florencio Zaragoza
Green, Esq. Reza
Higel Floyd D.
Novo Nordisk A S
Sackey Ebenezer
Waibel, Esq. Peter J.
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