Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-13
2003-11-04
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235500, C514S253010, C514S249000, C514S307000, C514S314000, C514S319000, C514S320000, C514S321000, C514S322000, C514S323000, C514S324000, C514S326000, C514S331000, C514S316000, C544S129000, C544S130000, C544S124000, C544S360000, C544S353000, C544S364000, C544S090000, C546S144000, C546S146000, C546S148000, C546S150000, C546S165000, C546S175000, C546S167000, C546S173000, C546S176000, C546S200000, C546S187000, C546S189000, C546S191000, C546S196000, C546S201000, C546S202000, C546S198000, C546S199000
Reexamination Certificate
active
06642228
ABSTRACT:
TECHNICAL FIELD
The present invention relates to antagonists having affinity for &agr;1B adrenoceptor.
BACKGROUND ART
Noradrenaline and adrenaline play important roles as neurotransmitters of the sympathetic nerve system or as vasoactive hormones in the regulation of physiological functions.
These noradrenaline and adrenaline transmit information into the cell by binding with receptors on a cell menbrane. The receptors were initially classified as a receptors and &bgr; receptors by Ahlquist (Am. J. Physiol., 153, 586(1948)), and thereafter, the &agr; receptors were classified as &agr;1 receptors and &agr;2 receptors, and the &bgr; receptors were classified as &bgr;1 receptor and &bgr;2 receptor.
Of these adrenoceptors, it has been cleared that &agr;1 receptors are important receptors which are associated with a variety of physiological activities such as vascular smooth muscle contraction, pupil dilator muscle contraction, cardiac muscle contraction, urethral smooth muscle contraction, renin secretion in the kidney, glycogenolysis in the liver, and lipolysis in fat cells.
The &agr;1 receptors have further been classified as three subtypes, &agr;1a, &agr;1b, and &agr;1d, by means of molecular biological techniques advanced in recent years (Pharmacol. Rev., 47, 267(1995)). Initially, there was some confusion between the molecular-biological classification using clones and the pharmacological classification, but the classification is now unified such that &agr;1a, &agr;1b, and &agr;1d receptors, which are classified based on clone receptors, respectively correspond to &agr;1A, &agr;1B, and &agr;1D receptors, which are pharmacologically classified.
Each of the &agr;1 receptor subtypes is considered to exhibit pharmacological and tissue specificities, and it is very important to provide compounds having selectivity for each of the &agr;1 receptor subtypes in order to elucidate physiological activities mediated by individual receptor subtypes and to remedy diseases in which they are involved.
Prazosin is widely used as a therapeutic agent for hypertension at present and has been already known to have no selectivity for the &agr;1 receptor subtypes. Then, a multiplicity of compounds have been synthetically obtained, and 5-methylurapidil and KMD-3213, for example, have been developed as compounds having high selectivity for &agr;1A receptor (Exp. Opin. Invest. Drugs, 6, 367(1997); Mol. Pharmacol., 48, 250(1995)). Experiments using these compounds having high selectivity for the &agr;1A receptor suggested that the &agr;1A receptor is deeply concerned in urethral smooth muscle contraction, and it is now under study to apply &agr;1A receptor antagonists as therapeutic agents for dysuria due to prostatic hypertrophy (New Current, 7, 14(1996)).
In contrast, there are very few reports on compounds e - having selectivity for the &agr;1B receptor, and spiperone and AH 1110A presently reported are not sufficient in their selectivity and affinity (Trend. Pharmacol. Sci., 15, 167(1994); Soc. Neurosci. Abstr., 20, 526(1994); J. Computer-Aided Mol. Design, 10, 545(1996)). Therefore, physiological activities mediated by the &agr;1B receptor have not yet been completely elucidated. However, recent experiments using &agr;1B transgenic mice have suggested that the &agr;1B receptor is involved in vascular muscle contraction, hypercardia, and tumorigenesis (Proc. Natl. Acad. Sci. USA, 87, 2896(1990); Proc. Natl. Acad. Sci. USA, 91, 10109(1994)). Additionally, experiments using &agr;1B receptor knock out mice have suggested that the &agr;1B receptor is involved in vasopressor responses (Proc. Natl. Acad. Sci. USA 94, 11589(1997)). Furthermore, a variety of experiments have reported that a stimulus to the &agr;1B receptor enhances the growth of vascular smooth muscle cells (J. Biol. Chem., 270, 30980(1995), and that there is a high possibility that the &agr;1B receptor is involved in contraction in human coronary artery and human cerebral artery induced by a stimulus to the &agr;1 receptors (“Kekkan to Naihi” (Blood Vessel and Endothelium), 6, 431(1996)), for example. Such &agr;1B receptor antagonists are expected as therapeutic agents for, for example, hypertension, high ocular tension, congestive heart failure, and arrhythmia (WO97/11698) . Consequently, demands are made to create compounds having affinity for the &agr;1B receptor and have high selectivity for the receptor, in order to create novel pharmaceutical agents.
The present invention therefore relates to &agr;1 adrenoceptor antagonists, and it is an object of the invention to provide antagonists which are selective for the &agr;1 receptor subtypes, and more specifically, to provide antagonists which have selectivity for the &agr;1B adrenoceptor.
DISCLOSURE OF INVENTION
The present invention relates to an &agr;1B adrenoceptor antagonist which includes a compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof:
[wherein Ar is indole, naphthalene, quinoline, benzimidazole, benzofuran, benzothiophene, benzisoxazole, or 2-ketobenzimidazoline, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 1 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
R
1
is hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, alkenyl having 2 to 9 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms;
B is a bond, or alkylene group having 1 to 3 carbon atoms which is unsubstituted or substituted with the groups selected from the group consisting of alkyl group having 1 to 8 carbon atoms, halogen, and hydroxy;
or B—N—R
1
forms a ring structure and is piperidine, piperazine, or 2,3,6-trihydropyridine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
n denotes an integer of 0 or 1;
A is alkylene having 2 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q is:
1) —NR
2
R
3
,
wh
Hayashi Ryoji
Isogaya Masafumi
Kumagai Hiroki
Moriwaki Mitsuhiro
Ohmori Eiji
Habte Kahsay
Shah Mukund J.
Toray Industries Inc.
LandOfFree
&agr;1b-adrenergic receptor antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with &agr;1b-adrenergic receptor antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and &agr;1b-adrenergic receptor antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3162361