Benzimidazole derivatives

Details Benzimidazole derivatives Benzimidazole derivatives

2001-11-05

2002-06-11

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06403626

ABSTRACT:

BACKGROUND OF THE INVENTION
Alpha adrenergic receptors are plasma membrane receptors which are located in the peripheral and central nervous systems throughout the body. They are members of a diverse family of structurally related receptors which contain seven putative helical domains and transduce signals by coupling to guanine nucleotide binding proteins (G-proteins). These receptors are important for controlling many physiological functions and, thus, have been important targets for drug development during the past 40 years. Examples of alpha adrenergic drugs include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma). However, most of these drugs produce undesirable side effects which may be due to the their interactions with other receptor subtypes. For example, clonidine is a well known centrally acting antihypertensive agent. However, it also produces untoward side effects such as analgesia, sedation, bradycardia and dry mouth which may be due to its lack of selectivity for a specific receptor subtype, i.e. &agr;
2
receptor.
Alpha adrenoceptors were originally proposed to have only two(alpha and beta) subtypes (Berthelsen, S.; Pethinger W. Life Sci. 1977, 21, 595). However, modern molecular biological and pharmacological techniques have led to the identification of at least 6 subtypes (&agr;
1a
, &agr;
1b
, &agr;
2a
, &agr;
2b
and &agr;
2c
) of the adrenoceptors (Bylund, D. B., Trends Pharmacol. Sci. 1988, 9, 356; Weinshank et al, U.S. Pat. No. 5,053,337, issued Oct. 1, 1991; Bard et al, International Publication No. WO 94/08040, published Apr. 14, 1994).
Among many other therapeutic indications, &agr;
2
receptors are believed to modulate pain and behavioral depression by regulating locus coeruleus firing. In addition, &agr;
2
receptors are well known to be involved in effects on blood pressure, heart rate, vasoconstriction and glaucoma. However, it is not known which therapeutic. indications are controlled by each of these subtypes.
The effects of alpha-2 receptor agonists on analgesia, anesthesia and sedation have been well documented for past 10 years (Pertovaara, A., Progress in Neurobiology, 1993, 40, 691). For example, systematic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proved effective in producing antinociception. Another alpha-2 agonist, Medetomidine, which has better alpha-2/alpha-1 selectivity and is more potent at alpha-2 receptors than clonidine, has been extensively studied for its antinociception effect. In the spinally-initiated heat-induced tail flick test in rats, systematic administration of medetomidine produced a dose-dependent antinociception which could be totally reversed by alpha-2 receptor antagonists, atipamazole or idazoxan. Experimental studies of medetomidine on pain sensitivity in humans also indicated that this agent is very effective on ischemic pains, even though effective drug doses were high enough to produce a sedation and considerable decrease in blood pressure.
Effects of alpha-2 receptor agonists in anaesthetic practice have also been investigated. The sedative effect of alpha-2 agonists is regarded as good component of premedication. Another beneficial effect of alpha-2 agonists in anaesthetic practice is their ability to potentiate the anaesthetic action of other agents and to reduce anaesthetic requirements of other drugs during surgery. Studies shows that premedication with 5 &mgr;g k
−1
of oral clonidine administration reduced fentanyl requirements for induction and intubation by 45% in patient undergoing aortocoronary bypass surgery (Ghingnone, M, et al, Anesthesiology 1986, 64, 36).
This invention is directed to novel benzimidazole derivatives which are selective for cloned human alpha 2 receptors. This invention is also related to uses of these compounds as analgesic, sedative and anaesthetic agents. In addition, this invention includes using such compounds for lowering intraocular pressure, and treatment of migraine, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemia, spasticity, diarrhea, nasal decongestion. Furthermore the compounds may be useful as cognition enhancers.
SUMMARY OF THE INVENTION
This invention provides compounds having the structure:
wherein each of R
1
, R
2
, R
3
and R
9
is independently H; straight chain or branched, substituted or unsubstituted C
1
-C
7
alkyl, C
2
-C
7
alkenyl or alkynyl; C
3
-C
7
cycloalkyl or cycloalkenyl; acyl, phenyl, substituted phenyl, or heteroaryl; wherein each dashed line represents a single bond or a double bond with the proviso that if R
1
is. present, R
3
is absent and there is a double bond between N at position 3 and C at position 2 and a single bond between C at position 2 and N at position 1 and if R
3
is present, R
1
is absent and there is a double bond between N at position 1 and C at position 2 and a single bond between C at position 2 and N at position 3; wherein each of R
4
, R
5
and R
6
is independently H, F, Cl, Br, I; straight chain or branched, substituted or unsubstituted C
1
-C
7
alkyl, C
2
-C
7
alkenyl or alkynyl; C
3
-C
7
cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl, —OH, —OR
7
, —CN, —COR
7
, —CO
2
R
7
, —CON (R
7
)
2
, —OCOR
7
, —SR
7
, —N (R
7
)
2
, —NR
7
COR
7
, —(CH
2
)
n
OR
7
, —( CH
2
)
n
N (R
7
)
2
, —(CH
2
)
n
NR
7
COR
7
, wherein n is an integer from 1 to 4; and wherein each of R
7
and R
8
is independently H; straight chain or branched, substituted or unsubstituted C
1
-C
7
alkyl, C
2
-C
7
alkenyl or alkynyl; phenyl or substituted phenyl.
These compounds are selective for cloned human alpha 2 receptors and are useful as analgesic, sedative or anaesthetic agents.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds having the structure:
where each of R
1
, R
2
, R
3
and R
9
is independently H; straight chain or branched, substituted or unsubstituted C
1
-C
7
alkyl, C
2
-C
7
alkenyl or alkynyl; C
3
-C
7
cycloalkyl or cycloalkenyl; acyl, phenyl, substituted phenyl, or heteroaryl; where each dashed line represents a single bond or a double bond with the proviso that if R
1
is present, R
3
is absent and there is a double bond between N at position 3 and C at position 2 and a single bond between C at position 2 and N at position 1 and if R
3
is present, R
1
is absent and there is a double bond between N at position 1 and C at position 2 and a single bond between C at position 2 and N at position 3; where each of R
4
, R
5
and R
6
is independently H, F, Cl, Br, I; straight chain or branched, substituted or unsubstituted C
1
-C
7
alkyl, C
2
-C
7
alkenyl or alkynyl; C
3
-C
7
cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl, —OH, —OR
7
, —CN, —COR
7
, —CO
2
R
7
, —CON(R
7
)
2
, —OCOR
7
, —SR
7
, —N(R
7
)
2
, —NR
7
COR
7
, —(CH
2
)
n
OR
7
, —(CH
2
)
n
N(R
7
)
2
, —(CH
2
)
n
NR
7
COR
7
, where n is an integer from 1 to 4; and where each of R
7
and R
8
is independently H; straight chain or branched, substituted or unsubstituted C
1
-C
7
alkyl, C
2
-C
7
alkenyl or alkynyl; phenyl or substituted phenyl.
The compound may have the following preferred structure:
where each of R
1
, R
2
, R
3
, R
4
and R
6
is defined above.
In addition, the invention further describes compounds having the following structures:
Acid salts of the compounds described above may be also be prepared. The acid salts may be but are not limited to the following HCl, HBr, HI, H
2
SO
4
, CH
3
COOH, CF
3
COOH, HNO
3
, CF
3
SO
3
H, CH
3
SO
3
H, C
4
H
4
O
4
, HO
2
CCH═CHCO
2
H, HO
2
CCH═CHCO
2
H, HO
2
CCH (OH) CH (OH) CO
2
H.
The invention also describes a pharmaceutical composition comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier.
The i

Affiliated with

Also associated with

Rating

Benzimidazole derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzimidazole derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazole derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2945784