U.S. patent application number 09/992947 was filed with the patent office on 2002-05-30 for novel benzimidazole derivatives.
This patent application is currently assigned to Synaptic Pharmaceutical Corporation. Invention is credited to Gluchowski, Charles, Jeon, Yoon T..
Application Number | 20020065307 09/992947 |
Document ID | / |
Family ID | 23096413 |
Filed Date | 2002-05-30 |
United States Patent
Application |
20020065307 |
Kind Code |
A1 |
Jeon, Yoon T. ; et
al. |
May 30, 2002 |
Novel benzimidazole derivatives
Abstract
This invention provides compounds having the structure: 1
wherein each of R.sub.1, R.sub.2, R.sub.3 and R.sub.9 is
independently H; straight chain or branched, substituted or
unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or
alkynyl; C.sub.3-C.sub.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.sub.1 is present, R.sub.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.sub.3 is
present, R.sub.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.sub.4, R.sub.5
and R.sub.6 is independently H, F, Cl, Br, I; straight chain or
branched, substituted or unsubstituted C.sub.1-C.sub.7 alkyl,
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or
cycloalkenyl; phenyl, substituted phenyl, heteroaryl, --OH,
--OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7,
--(CH.sub.2).sub.nN(R.su- b.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4; and wherein each of R.sub.7 and R.sub.8 is independently H;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.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.
Inventors: |
Jeon, Yoon T.; (Ridgewood,
NJ) ; Gluchowski, Charles; (Wayne, NJ) |
Correspondence
Address: |
John P. White
Cooper & Dunham LLP
1185 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
Synaptic Pharmaceutical
Corporation
|
Family ID: |
23096413 |
Appl. No.: |
09/992947 |
Filed: |
November 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09992947 |
Nov 5, 2001 |
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09232490 |
Jan 15, 1999 |
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6316637 |
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09232490 |
Jan 15, 1999 |
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08765656 |
Mar 25, 1997 |
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08765656 |
Mar 25, 1997 |
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PCT/US95/09895 |
Aug 4, 1995 |
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08765656 |
Mar 25, 1997 |
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08285956 |
Aug 4, 1994 |
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Current U.S.
Class: |
514/370 ;
548/198 |
Current CPC
Class: |
C07D 403/12
20130101 |
Class at
Publication: |
514/370 ;
548/198 |
International
Class: |
A61K 031/427; C07D
417/02 |
Claims
What is claimed is:
1. A compound having the structure: 13wherein each of R.sub.1,
R.sub.2, R.sub.3 and R.sub.9 is independently H; straight chain or
branched, substituted or unsubstituted C.sub.1-C.sub.7 alkyl,
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.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.sub.1 is present, R.sub.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.sub.3 is present, R.sub.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.sub.4, R.sub.5 and R.sub.6 is independently H, F, Cl, Br, I;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted
phenyl, heteroaryl, --OH, --OR,, --CN, --COR.sub.1,
--CO.sub.2R.sub.7, --CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7,
--N(R.sub.7).sub.2, --NR.sub.7COR.sub.7,
--(CH.sub.2).sub.nOR.sub.7, --(CH.sub.2).sub.rN(R.su- b.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4; and wherein each of R.sub.7 and R.sub.9 is independently H;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; phenyl
or substituted phenyl.
2. A compound having the structure: 14wherein each of R.sub.1,
R.sub.2 and R.sub.3 is independently H; straight chain or branched,
substituted or unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or cycloalkenyl;
acyl, phenyl, substituted phenyl, or heteroaryl; and wherein each
of R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I; straight
chain or branched, substituted or unsubstituted C.sub.1-C.sub.7
alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl,
--OH, --OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7,
--(CH.sub.2).sub.nN(R.sub.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4.
3. The compound of claim 1, wherein R.sub.4 is H.
4. The compound of claim 1, wherein R.sub.4 is Br.
5. The compound of claim 1, wherein R.sub.4 is Cl.
6. The compound of claim 1, wherein R.sub.4 is CH.sub.3.
7. The compound of claim 1, wherein R.sub.6 is Cl.
8. The compound of claim 1, wherein R.sub.6 is CH.sub.3.
9. The compound of claim 1, wherein R.sub.4 is Br and R.sub.6 is
Cl.
10. The compound of claim 1, wherein R.sub.4 and R.sub.6 are both
Cl.
11. The compound of claim 1, wherein R.sub.1 is CH(CH.sub.3).sub.2
and R.sub.4 is Br.
12. The compound of claim 1, wherein R.sub.2 is CH(CH.sub.3).sub.2
and R.sub.4 is Br.
13. The compound of claim 1 having the structure: 15
14. The compound of claim 1 having the structure: 16
15. The compound of claim 1 having the structure: 17
16. The compound of claim 1 having the structure: 18
17. The compound of claim 1 having the structure: 19
18. The compound of claim 1 having the structure: 20
19. The compound of claim 1 having the structure: 21
20. The compound of claim 1 having the structure: 22
21. The compound of claim 1 having the structure: 23
22. The compound of claim 1 having the structure: 24
23. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claims 1 or 2 and a
pharmaceutically acceptable carrier.
24. A method for treating an alpha-2 adrenergic receptor associated
disorder in a subject which comprises administering to the subject
an amount of a compound having the structure: 25wherein each of
R.sub.1, R.sub.2, R.sub.3 and R.sub.9 is independently H; straight
chain or branched, substituted or is unsubstituted C.sub.1-C.sub.7
alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.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.sub.1 is present, R.sub.3 is
absent and there is a double bond between N at position 1 and and C
at position 2 and a single bond between C at position 2 and N at
position 3 and if R.sub.3 is present, R.sub.2 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; wherein
each of R.sub.4, R.sub.5 and R.sub.6 is independently H, F, Cl, Br,
I; straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl or cycloalkenyl; phenyl, substituted
phenyl, heteroaryl, --OH, --OR.sub.7, --CN, --COR.sub.7,
--CO.sub.2R.sub.7, --CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7,
--N(R.sub.7).sub.2, --NR.sub.7COR.sub.7, --(CH.sub.2) OR.sub.7,
--(CH.sub.2).sub.nN(R.sub.7).- sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4; and wherein each of R.sub.7 and R.sub.8 is independently H;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; phenyl
or substituted phenyl.
25. The method of claim 24, wherein the compound administered to
the subject has the structure: 26wherein each of R.sub.1, R.sub.2
and R.sub.3 is independently H; straight chain or branched,
substituted or unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or cycloalkenyl;
acyl, phenyl, substituted phenyl, or heteroaryl; wherein each of
R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I; straight
chain or branched, substituted or unsubstituted C.sub.1-C.sub.7
alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl,
--OH, --OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7,
--(CH.sub.2).sub.n(R.sub- .7).sub.2,
(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4.
26. A method for alleviating pain in a subject which comprises
administering to the subject an amount of a compound having the
structure: 27wherein each of R.sub.1, R.sub.2, R.sub.3 and R.sub.9
is independently H; straight chain or branched, substituted or
unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or
alkynyl; C.sub.3-C.sub.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.sub.1 is present, R.sub.3 is absent and there is a double bond
between N at position 1 and and C at position 2 and a single bond
between C at position 2 and N at position 3 and if R.sub.3 is
present, R.sub.1 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; wherein each of R.sub.4, R.sub.5
and R.sub.6 is independently H, F, Cl, Br, I; straight chain or
branched, substituted or unsubstituted C.sub.1-C.sub.7 alkyl,
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or
cycloalkenyl; phenyl, substituted phenyl, heteroaryl, --OH,
--OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7
--(CH.sub.2).sub.nN(R.sub.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4; and wherein each of R.sub.7 and R.sub.8 is independently H;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; phenyl
or substituted phenyl.
27. The method of claim 26, wherein the compound administered to
the subject has the structure: 28wherein each of R.sub.1, R.sub.2
and R.sub.3 is independently H; straight chain or branched,
substituted or unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or cycloalkenyl;
acyl, phenyl, substituted phenyl, or heteroaryl; wherein each of
R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I; straight
chain or branched, substituted or unsubstituted C.sub.1-C.sub.7
alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl,
--OH, --OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7,
--(CH.sub.2).sub.nN(R.su- b.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4.
28. The method of claim 27, wherein the compound administered to
the subject has the structure: 29
Description
BACKGROUND OF THE INVENTION
[0001] This application is a continuation-in-part of U.S. Ser. No.
08/285,956 filed Aug. 4, 1994, the contents of which are
incorporated by reference. Throughout this application, various
references are referred to within parentheses. Disclosure of these
publications in their entireties are hereby incorporated by
reference into this application to more fully describe the state of
the art to which this invention pertains.
[0002] 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. .alpha..sub.2 receptor.
[0003] 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 (.alpha..sub.1a, .alpha..sub.1b, .alpha..sub.1c,
.alpha..sub.2a, .alpha..sub.2b and .alpha..sub.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).
[0004] Among many other therapeutic indications, .alpha..sub.2
receptors are believed to modulate pain- and behavioral depression
by regulating locus coeruleus firing. In addition, .alpha..sub.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.
[0005] 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.
[0006] 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 .mu.g kg.sup.-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).
[0007] 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
[0008] This invention provides compounds having the structure:
2
[0009] wherein each of R.sub.1, R.sub.2, R.sub.3 and R.sub.9 is
independently H; straight chain or branched, substituted or
unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or
alkynyl; C.sub.3-C.sub.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.sub.1 is present, R.sub.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.sub.3 is
present, R.sub.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.sub.4, R.sub.5
and R.sub.6 is independently H, F, Cl, Br, I; straight chain or
branched, substituted or unsubstituted C.sub.1-C.sub.7 alkyl,
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or
cycloalkenyl; phenyl, substituted phenyl, heteroaryl, --OH,
--OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7,
--(CH.sub.2).sub.nN(R.sub.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, wherein n is an integer from 1
to 4; and wherein each of R.sub.7 and R.sub.8 is independently H;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; phenyl
or substituted phenyl.
[0010] These compounds are selective for cloned human alpha 2
receptors and are useful as analgesic, sedative or anaesthetic
agents.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention is directed to compounds having the
structure: 3
[0012] where each of R.sub.1, R.sub.2, R.sub.3 and R.sub.9 is
independently H; straight chain or branched, substituted or
unsubstituted C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or
alkynyl; C.sub.3-C.sub.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.sub.1 is present, R.sub.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.sub.3 is
present, R.sub.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.sub.4, R.sub.5 and
R.sub.6 is independently H, F, Cl, Br, I; straight chain or
branched, substituted or unsubstituted C.sub.1-C.sub.7 alkyl,
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl or
cycloalkenyl; phenyl, substituted phenyl, heteroaryl, --OH,
--OR.sub.7, --CN, --COR.sub.7, --CO.sub.2R.sub.7,
--CON(R.sub.7).sub.2, --OCOR.sub.7, --SR.sub.7, --N(R.sub.7).sub.2,
--NR.sub.7COR.sub.7, --(CH.sub.2).sub.nOR.sub.7,
--(CH.sub.2).sub.nN(R.sub.7).sub.2,
--(CH.sub.2).sub.nNR.sub.7COR.sub.7, where n is an integer from 1
to 4; and where each of R.sub.7 and R.sub.8 is independently H;
straight chain or branched, substituted or unsubstituted
C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.7 alkenyl or alkynyl; phenyl
or substituted phenyl.
[0013] The compound may have the following preferred structure:
4
[0014] where each of R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.6
is defined above.
[0015] In addition, the invention further describes compounds
having the following structures: 5
[0016] 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.sub.2SO.sub.4, CH.sub.3COOH,
CF.sub.3COOH, HNO.sub.3, CF.sub.3SO.sub.3H, CH.sub.3SO.sub.3H,
C.sub.4H.sub.4O.sub.4, HO.sub.2CCH.dbd.CHCO.sub.2H,
HO.sub.2CCH.dbd.CHCO.sub.2H, HO.sub.2CCH(OH)CH(OH)CO.sub.2H.
[0017] The invention also describes a pharmaceutical composition
comprising a therapeutically effective amount of the compounds
described above and a pharmaceutically acceptable carrier.
[0018] The invention further describes a method for treating an
alpha-2 adrenergic receptor associated disorder or alleviating pain
in a subject which comprises administering to the subject an amount
of a compound having the structure: 6
[0019] where each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8 and R.sub.9 is defined above.
[0020] The invention describes a method for treating an alpha-2
adrenergic receptor associated disorder or alleviating pain in a
subject which comprises administering to the subject an amount of a
compound having the structure: 7
[0021] where each of R.sub.1, R.sub.2, R.sub.3, R.sub.4and R.sub.6
is defined above.
[0022] The invention describes a method for alleviating pain in a
subject which comprises administering to the subject an amount of a
compound having the structure: 8
[0023] The method described above may be used to treat alpha-2
adrenergic receptor associated disorders such as hypertension,
rheumatoid arthritis, ischemia, spasticity, glaucoma, migraines,
alcohol withdrawal, drug addiction, diarrhea, or nasal
congestion.
[0024] The compounds may be administered to a subject suffering
from an alpha-2 adrenergic receptor associated disorder. The
effective quantity of the compounds described above is from about
0.01 mg/dose to about 10 mg/dose and preferably from about 0.1
mg/dose to about 20 mg/dose. Such dose levels will depend upon the
half-life of the compounds see for example Goodman and Gilman's
"The Pharmacological Basis of Therapeutics," Eighth Edition, 1990,
Pergamon Press, pages 3-32.
[0025] Administration for the above compounds may be by any
conventional route of administration, including, but not limited
to, intravenous, intramuscular, oral, ophthalmic, subcutaneous,
intratumoral, intradermal, and parenteral.
[0026] The present invention also provides compounds useful for
preparing a pharmaceutical composition comprising any of the
compounds disclosed herein and a pharmaceutically acceptable
carrier. The composition may contain between 0.1 mg and 500 mg of
any of the compounds, and may be constituted in any form suitable
for the mode of administration selected.
[0027] The compounds may be administered neat or with a
pharmaceutical carrier to a patient in need thereof. The
pharmaceutical carrier may be solid or liquid.
[0028] A solid carrier can include one or more substances which may
also act as flavoring agents, lubricants, solubilizers, suspending
agents, fillers, glidants, compression aids, binders or
tablet-disintegrating agents; it can also be an encapsulating
material. In powders, the carrier is a finely divided solid which
is in admixture with the finely divided active ingredient. In
tablets, the active ingredient is mixed with a carrier having the
necessary compression properties in suitable proportions and
compacted in the shape and size desired.
[0029] The powders and tablets preferably contain up to 99% of the
active ingredient. Suitable solid carriers include, for example,
calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low
melting waxes and ion exchange resins.
[0030] Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved or suspended
in a pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fats. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(partially containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are useful in sterile
liquid form compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated hydrocarbon
or other pharmaceutically acceptable propellent.
[0031] Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously.
[0032] The compounds may be prepared as a sterile solid composition
which may be dissolved or suspended at the time of administration
using sterile water, saline, or other appropriate sterile
injectable medium. Carriers are intended to include necessary and
inert binders, suspending agents, lubricants, flavorants,
sweeteners, preservatives, dyes, and coatings.
[0033] The compound can be administered orally in the form of a
sterile solution or suspension containing other solutes or
suspending agents, for example, enough saline or glucose to make
the solution isotonic, bile salts, acacia, gelatin, sorbitan
monoleate, polysorbate 80 (oleate esters of sorbitol and its
anhydrides copolymerized with ethylene oxide) and the like.
[0034] The compound can also be administered orally either in
liquid or solid composition form. Compositions suitable for oral
administration include solid forms, such as pills, capsules,
granules, tablets, and powders, and liquid forms, such as
solutions, syrups, elixirs, and suspensions. Forms useful for
parenteral administration include sterile solutions, emulsions, and
suspensions.
[0035] Optimal dosages to be administered may be determined by
those skilled in the art, and will vary with the particular
compound in use, the strength of the preparation, the mode of
administration, and the advancement of the disease condition.
Additional factors depending on the particular subject being
treated will result in a need to adjust dosages, including subject
age, weight, gender, diet, and time of administration.
[0036] This invention will be better understood from the
Experimental Details which follow. However, one skilled in the art
will readily appreciate that the specific methods and results
discussed are merely illustrative of the invention as described
more fully in the claims which follow thereafter.
[0037] Experimental Details
[0038] General Methods
[0039] Four general synthetic methods were used to synthesize the
compounds described herein. These methods are illustrated in
Reaction Schemes 1-4.
[0040] The compounds herein have been prepared using synthetic
sequences shown in Schemes 1-4. C-4 halogen substituted
5-aminobenzimidazoles were obtained from commercially available
5-nitrobenzimidazole by the sequence of hydrogenation and
halogenation. C-4 alkyl substituted analogs were prepared in a
similar reaction sequence in which alkyl group was incorporated
using a Grignard reaction (Scheme 1). Reaction of
5-aminobenzimidazole with 2-imidazoline-2-sulfonic acid (ISA) which
was obtained from 2-imidazolinethione (Gluchowski, C. U.S. Pat. No.
5,130,441) provides access to 2-aminoimidazolines in high yield (45
-95%). C-2 substituted 5-nitrobenzimidazoles were prepared by
condensation of 4-nitro-1,2-phenylenediamine with corresponding
acids (Scheme 2). C-2 substituted 5-nitrobenzimidazoles were
subjected to the same reaction sequence as Scheme 1 to provide the
desired final product. Reaction of alkyl halides with
5-nitrobenzimidazole in the presence of NaH provided both N-1 and
N-3 substituted benzimidazoles (Scheme 3). The reaction mixtures
were subjected to hydrogenation (H.sub.2/Pd-C) to produce the
corresponding amines, which were separated on column
chromatography. Each amine was subjected to the reaction sequence
described in Scheme 1 to provide the final product.
[0041] Preparation of C-7 substituted benzimidazoles is illustrated
in Scheme 4. Halogenation of 2,4-dinitroaniline provided 6-halogen
substituted anilines, which were subjected to hydrogenation and
condensation in formic acid to provide 7-halosubstituted
5-aminobenzimidazoles. These intermediates were coupled to ISA to
provide the desired products. C-7 alkyl substituted benzimidazoles
were prepared using a similar sequence of reactions. Accordingly,
6-bromo-2,4-dinitroaniline was converted to 6-alkyl or aryl
substituted analogs by the Pd(II) catalyzed coupling reaction.
Conversion of alkyl substituted anilines to benzimidazoles was
carried out in same reaction sequences described in Scheme 2. 9 10
11 12
EXAMPLE 1
5-(2-Imidazolin-2-ylamino)benzimidazole (#1)
[0042] 5-Aminobenzimidazole. A solution of 5-nitrobenzimidazole
(4.0 g, 25 mmol) and 10% Pd/C (0.5 g) was stirred under H.sub.2 for
12 h. The reaction mixture was filtered through Celite-assisted
funnel and concentrated in vacuo, yielding 3.2 g (25 mmol, >95%)
of the desired product, which was characterized by NMR and
subjected to following reactions without further purification.
[0043] 2-Imidazoline-2-sulfonic acid (ISA). ISA was prepared
according to the procedure described in literature (Gluchowski, C.
U.S. Pat. No. 5,130,441, 1992). To a solution of
2-imidazolinethione (6.6 g, 65 mmol), sodium molybdate(IV)
dihydrate (0.5 g, 2.1 mmol) and NaCl (1.5 g) in 150 ml of distilled
water was added 30% of H.sub.2O.sub.2 (50 ml, 450 mmol) for 1 h at
-10.degree. C. The reaction mixture was stored at -20.degree. C.
for 12 h and then reaction temperature was slowly warmed up to
25.degree. C. The white crystal obtained was filtered and dried in
vacuo to provide 2.8 g (21 mmol, 32%) of the acid. The compound was
used in the examples noted below.
[0044] 5-(2-Imidazolin-2-ylamino)benzimidazole. A solution of
5-aminobenzimidazole (1.0 g, 7.5 mmol) and ISA (2.5 g, 18.8 mmol)
in 10 ml of isobutanol was stirred at reflux for 12 h. The reaction
mixture was concentrated in vacuo to yield an oily residue which
was subjected to silica gel column chromatography (20% NH.sub.3
sat'd MeOH/EtOAc) to produce 0.77 g (3.8 mmol, 53%) of the product.
The product obtained was converted to the fumarate salt and
recrystallized from MeOH to afford 0.21 g (27%) of the product as a
white solid: mp 196-198.degree. C.; Anal. Calc. for
C.sub.10H.sub.11N.sub.5.1.0C.sub.4H.sub.4O.sub.4.1.3H.sub- .2O
requires C, 49.62; H, 4.65; N, 20.67. Found: C, 49.65; H, 5.73; N,
20.53.
EXAMPLE 2
4-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#2)
[0045] 4-Bromo-5-aminobenzimidazole. To a solution of
5-aminobenzimidazole (3.3 g, 2.3 mmol) in 30 ml of AcOH was added
bromine. (0.055 ml, 1.1 mmol) in a portion and resulting reaction
mixture was stirred for 0.5 h at 25.degree. C. Reaction mixture was
concentrated in vacuo, yielding a dark brown solid which was
subjected to silica gel column chromatography (NH.sub.3 saturated
10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired
product.
[0046] 4-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A solution
of 4-bromo-5-aminobenzimidazole (0.22 g, 0.97 mmol) and ISA (0.34
g, 2.5 mmol) in 5 ml of isobutanol was stirred at reflux for 12 h.
Reaction mixture was concentrated in vacuo and subjected to silica
gel column chromatography (NH.sub.3 saturated 20% MeOH/EtOAc) to
yield 0.23 g (0.83 mmol, 84%) of the product. The product obtained
was converted to the fumarate salt and recrystallized from MeOH to
afford 0.12 g (30%) of the product as a white solid: mp
199-202.degree. C.; Anal. Calc. for
C.sub.10H.sub.10N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4. 0.7H.sub.2O
requires C, 41.13; H, 3.80; N, 17.13. Found: C, 41.60; H, 3.81; N,
16.97.
EXAMPLE 3
4-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole (#3)
[0047] 4-Chloro-5-aminobenzimidazole. To a solution of
5-aminobenzimidazole (1.0 g, 7.5 mmol) in 20 ml of AcOH was added
Cl.sub.2 saturated AcOH solution until it produced a precipitation.
The reaction mixture was concentrated in vacuo, yielding a dark
residue which was subjected to column chromatography (NH.sub.3
sat'd 30% MeOH/EtOAc) to yield 120 mg (0.72 mmol) of
4-chloro-5-aminobenzimidazole.
[0048] 4-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole. The amine
(120 mg, 0.72 mmol) was mixed with ISA (250 mg, 1.8 mmol), and
resulting mixture was stirred for 12 h at reflux. Column
chromatographic separation (NH.sub.3 sat'd 30% MeOH/EtOAc) of the
reaction mixture yielded 140 mg (0.62 mmol, 87%) of the desired
product. The product obtained was converted to the fumarate salt
and recrystallized from EtOH to afford 50 mg (20%) of the product
as a white solid: mp 207-208.degree. C.; Anal. Calc. for
C.sub.10H.sub.10N.sub.5Cl.1.0C.sub.4H.sub.4O.sub.4.0.6H.sub.2O
requires C, 46.38; H 4.23; N, 19.32. Found: C, 46.32; H. 4.23; N,
19.47.
EXAMPLE 4
4-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#4)
[0049] 4-Methyl-5-aminobenzimidazole. A solution of
4-bromo-5-aminobenzimidazole (180 mg, 0.84 mmol), tetramethyltin
(330 mg, 2.4 mmol) and bis(triphenylphosphine)palladium (II)
chloride (20 mg) in 5 ml of anhydrous DMF was placed in sealed tube
and stirred for 12 h at 145.degree. C. The reaction mixture was
concentrated in vacuo, yielding an oily residue which was subjected
to column chromatographic separation (NH.sub.3 sat'd 10%
MeOH/EtOAc) to yield 140 mg (0.83 mmol, >95%) of
4-methyl-5-aminobenzimidazole.
[0050] 4-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. The amine
obtained was placed in flask with ISA (0.38 g, 2.5 mmol) and 5 ml
of isobutanol, and resulting mixture was stirred at reflux for 12
h. Column chromatographic separation (NH.sub.3 sat'd 10%
MeOH/EtOAc) of the reaction mixture provided 0.15 g (0.71 mmol,
84%) of the desired product. The product obtained was converted to
the fumarate salt and recrystallized from MeOH to afford 92 mg
(25%) of the product as a white solid: mp 155-157.degree. C.; Anal.
Calc. for C.sub.11H.sub.13N.sub.5.1.5-
C.sub.4H.sub.4O.sub.4.0.5H.sub.2O requires C, 52.08; H, 4.96; N,
17.86. Found: C, 52.08; H. 4.97; N, 17.80.
EXAMPLE 5
4-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole (#5)
[0051] 4-iodo-5-aminobenzimidazole. To a solution of
5-aminobenzimidazole (0.6 g, 4.5 mmol) and Hg(OAc).sub.2 (1.72 g,
5.5 mmol) in 20 ml of AcOH was added a solution of I.sub.2 until
solution produces a precipitation. The reaction mixture was
concentrated in vacuo, yielding an oily residue which was subjected
to column chromatographic separation (NH.sub.3 sat'd 10%
MeOH/EtOAc) to produce 0.30 (1.2 mmol, 26%) g of
4-iodo-5-aminobenzimidazole.
[0052] 4-Iodo-5- (2-imidazolin-2-ylamino)benzimidazole. A solution
of the amine (0.30 g, 1.1 mmol) and ISA (0.62 g, 4.4 mmol) was
stirred at reflux for 12 h. Column chromatographic separation of
the reaction mixture (NH.sub.3 sat'd 20% MeOH/EtOAc) provided 0.12
g (0.34 mmol, 31%) of the desired product. The product obtained was
converted to the fumarate salt and recrystallized from EtOH to
afford 0.12 g (20%) of the product as a white solid: mp 256.degree.
C.; Anal. Calc. for C.sub.10H.sub.10N.sub.5I.-
2.0C.sub.4H.sub.4O.sub.4.1.0H.sub.2C requires C, 37.45; H, 3.49; N,
12.13. Found: C, 37.52; H, 3.51; N, 12.62.
EXAMPLE 6
4-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole (#6)
[0053] 4-Ethyl-5-aminobenzimidazole. To a solution of
5-nitro-benzimidazole (2.8 g, 17 mmol) in THF was added 16 ml of
EtMgBr solution (48 mmol) and reaction mixture was stirred for 2 h
at -15.degree. C. A solution of tetrachloro-1,4-benzoquinone (8.8
g, 36 mmol) in THF was added dropwise into reaction mixture, which
was allowed to warm up to 25.degree. C. over 1 h. Silica gel (20 g)
was added into reaction mixture and solvent was removed in vacuo to
provide a brown silica gel powder which was subjected to column
chromatography (EtOAc, neat) to provide 1.7 g (8.9 mmol, 52%) of
4-ethyl-5-nitrobenzimidazole, which was subsequently subjected to
hydrogenation (H.sub.2, Pd/C) to yield 1.32 g (8.2 mmol) of
4-ethyl-5-aminobenzimidazole.
[0054] 4-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution
of the amine (0.71 g, 4.3 mmol) and ISA (0.75 g, 5.6 mmol) in 10 ml
of isobutanol was stirred at reflux for 12 h. The reaction mixture
was concentrated in vacuo, yielding an oil, which was subjected to
column chromatography (NH.sub.3 sat'd 30% EtOH/EtOAc) to yield 0.26
g (1.2 mmol, 28%) of the desired product. The product obtained was
converted to the fumarate salt and recrystallized from MeOH to
afford 0.22 g (16%) of the product as a light brown solid: mp
238-239.degree. C.; Anal. Calc. for
C.sub.12H.sub.15N.sub.4.1.0C.sub.4H.sub.4O.sub.4 requires C, 55.60;
H, 5.55; N, 20.28. Found: C, 54.63; H, 5.70; N, 19.46.
EXAMPLE 7
4-n-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole (#7)
[0055] 4-n-Propyl-5-aminobenzimidazole. To a solution of
5-nitrobenzimidazole (2.3 g, 14 mmol) was added 14 ml of n-PrMgBr
solution (42 mmol) and reaction mixture was stirred for 2 h at
-15.degree. C. The reaction was quenched by adding a solution of
tetrachloro-1,4-benzoquinone (4 g, 16 mmol) in 10 ml of THF. The
reaction mixture was concentrated in vacuo to provide an oil, which
was subjected to column chromatographic separation (EtOAc, neat) to
provide 1.4 g (7.2 mmol, 52%) of 4-n-propyl-5-nitrobenzimidazole,
which was converted to the corresponding amine (1.2 g, >95%) by
hydrogenation (H.sub.2, Pd/C).
[0056] 4-n-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole. The
amine (1.2 g, 14 mmol) was stirred with ISA (1.5 g, 11.2 mmol) at
reflux for 12 h. Concentration of reaction mixture produced an oily
residue, which was subjected to column chromatographic separation
(NH.sub.3 sat'd 30% MeOH/EtOAc) to provide 0.63 g (2.6 mmol, 37%)
of the desired product. The product obtained was converted to the
fumarate salt and recrystallized from EtOH to afford 0.45 g (16%)
of the product as a light brown solid: mp 229-230.degree. C.
EXAMPLE 8
4-n-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole (#8)
[0057] 4-n-Butyl-5-aminobenzimidazole. To a solution of
5-nitrobenzimidazole (0.41 g, 2.5 mmol) was added a solution of
n-BuLi (7.5 mmol) and reaction mixture was stirred for 1 h at
0.degree. C. The reaction mixture was quenched by adding a few
drops of H.sub.2O and concentrated in vacuo yielding an oil which
was subjected to silica gel column chromatography (5% MeOH/EtOAC)
to provide 0.13 g of 4-n-butyl-5-nitrobenzimidazole and 0.19 g of
4-n-butyl-5-aminobenzimidazo- le. The nitrobenzimidazole was
converted to the amine in hydrogenation (H.sub.2/Pd-C) to provide
0.28 g (1.5 mmol, 60%) of the desired product.
[0058] 4-n-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole. The amine
(0.28 g, 1.5 mmol) was refluxed with ISA (0.50 g, 3.7 mmol) in
isobutanol for 12 h. Column chromatographic separation of reaction
mixture (NH.sub.3 sat'd 20% MeOH/EtOAc) provided 0.21 g (0.81 mmol,
54%) of the product. The product obtained was converted to the
fumarate salt and recrystallized from isopropanol to afford 0.38 g
(49%) of the product as a foamy solid: mp 96.degree. C.; Anal.
Calc. for C.sub.14H.sub.19N.sub.5.- 2.0C.sub.4H.sub.4O.sub.4.
requires C, 55.68; H, 5.86; N, 16.23. Found: C, 55.98; H, 5.68; N,
16.49.
EXAMPLE 9
1-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#9)
[0059] 1- and 3-Methyl-5-aminobenzimidazole. A solution of
5-nitrobenzimidazole (3.0 g, 18.4 mmol) in 100 ml of THF was
stirred with NaH (2.7 g, 36.8 mmol) for 0.5 h at 25.degree. C. To
the solution was added methyl iodide (2.0 ml, 20.3 mmol) and
resulting mixture was stirred for 12 h. The reaction mixture was
concentrated in vacuo to provide an oil, which was dissolved in 200
ml of MeOH and stirred with 0.3 g of 10% Pd/C under H.sub.2 for 12
h. The reaction mixture was filtered and concentrated in vacuo,
yielding a dark oily residue which was subjected to column
chromatography (3% MeOH/CHCl.sub.3) to provide 0.69 g (3.9 mmol,
21%) of 1-methyl-5-aminobenzimidazole and 0.36 g (2.0 mmol, 11%) of
3-methyl-5-aminobenzimidazole.
[0060] 1-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole A solution
of 1-methyl-5-aminobenzimidazole (0.15 g, 1.1 mmol) and ISA (0.30
g, 2.2 mmol) in 3 ml of isobutanol was stirred at reflux for 12 h.
The reaction mixture was concentrated in vacuo, yielding an oily
residue which was purified on silica gel column chromatography
(NH.sub.3 sat'd 20% isopropanol/EtOAc) to yield 0.12 g (0.56 mmol,
51%) of the desired product. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.11 g (30%) of the product as a white crystal: mp 210-211.degree.
C.; Anal. Calc. for
C.sub.11H.sub.13N.sub.5.1.0C.sub.4H.sub.4O.sub.4.0.3H.sub.2O
requires C, 35.36; H, 5.28; N,20.74. Found: C, 53.67; H, 5.13; N,
20.70.
EXAMPLE 10
1-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#10)
[0061] 1-Methyl-4-bromo-5-aminobenzimidazole. To a solution of
1-methyl-5-aminobenzimidazole (0.36 g, 2.4 mmol) in 10 ml of AcOH
was added Br.sub.2 (0.12 ml). The reaction mixture was stirred for
1 h at 25.degree. C. and concentrated in vacuo, yielding an oil
which was subjected to column chromatography (NH.sub.3 sat'd 3%
MeOH/CHCl.sub.3) to yield 0.27 g (1.2 mmol, 50%) of the desired
product.
[0062] 1-Methyl-4-bromo-5- (2-imidazolin-2-ylamino)benzimidazole.
Isobutanolic solution of the amine (0.27 g, 1.2 mmol) and ISA (0.6
g, 4.5 mmol) was stirred at reflux for 12 h. The reaction mixture
was concentrated in vacuo, yielding an oily residue which was
subjected to column chromatography (NH.sub.3 sat'd 20% MeOH/EtOAc)
to yield 0.33 g (1.1 mmol, 92%) of the expected product. The
product obtained was recrystallized from EtOH to afford 0.21 g
(64%) of the product as a white crystal: mp 237-238.degree. C.;
Anal. Calc. for C.sub.11H.sub.12N.sub.5Br- .1.75H.sub.2O requires
C, 40.57; H, 4.80; N, 21.50. Found: C, 40.98; H, 4.81; N,
21.41.
EXAMPLE 11
3-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. (#11)
[0063] A solution of 3-methyl-5-aminobenzimidazole (0.20 g, 1.5
mmol) and ISA (0.45 g, 3.4 mmol) was stirred at reflux for 12 h.
The reaction mixture was concentrated in vacuo and purified on
column chromatography (NH.sub.3 sat'd 20% MeOH/EtOAc) to yield 0.19
g (0.88 mmol, 59%) of the product. The product obtained was
converted to the fumarate salt and recrystallized from MeOH to
afford 0.31 g (46%) of the product as a white crystal: mp
202-204.degree. C.; Anal. Calc. for C.sub.11H.sub.13N.sub.5.2-
.0C.sub.4H.sub.4O.sub.4 requires C, 51.01; H, 4.73; N,15.65. Found:
C, 51.65; H, 4.76; N, 15.78.
EXAMPLE 12
3-Methyl-4-bromo-5-(imidazolin-2-ylamino)benzimidazole (#12)
[0064] 3-Methyl-4-bromo-5-aminobenzimidazole. To a solution of
3-methyl-5-aminobenzimidazole (0.27 g, 1.8 mmol) in 10 ml of AcOH
was added Br.sub.2 (0.10 ml). The reaction mixture was stirred for
1 h at 25.degree. C. and concentrated in vacuo, yielding an oil
which was subjected to column chromatography (NH.sub.3 sat'd 3%
MeOH/CHCl.sub.3) to yield 0.14 g (0.62 mmol, 35%) of the desired
product.
[0065] 3-Methyl-4-bromo-5-(imidazolin-2-ylamino)benzimidazole. A
solution of 3-methyl-4-bromo-5-aminobenzimidazole (0.31 g, 1.4
mmol) and ISA (0.6 g, 4.5 mmol) in 10 ml of isobutanol was stirred
at reflux for 12 h. Oily residue obtained was subjected to column
chromatography (NH.sub.3 sat'd 20% isopropanol/EtOAc) to yield 0.39
g (1.3 mmol, 93%) of the desired product. The product obtained was
converted to the fumarate salt and recrystallized from MeOH to
afford 0.50 g (68%) of the product as a white solid: mp
209-210.degree. C.; Anal. Calc. for C.sub.11H.sub.12N.sub.5Br.2-
.0C.sub.4H.sub.4O.sub.4. requires C, 43.36; H, 3.83; N, 13.31.
Found: C, 43.66; H, 3.84; N, 13.10.
EXAMPLE 13
1-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole (#13)
[0066] 1- and 3-Propyl-5-aminobenzimidazole. A solution of
5-nitrobenzimidazole (3.6 g, 23 mmol) in 100 ml of THF was stirred
with NaH (1.5 g, 33 mmol) for 0.5 h at 25.degree. C. To the
solution was added allyl bromide (4.8 ml, 57 mmol) and resulting
mixture was stirred for 12 h. The reaction mixture was concentrated
in vacuo to provide an oil, which was subjected to column
chromatography to yield 4.0 g (19.7 mmol, 89%) of a mixture of 1-
and 3-allyl-5-nitrobenzimidazole. The nitrobenzimidazole mixture
was stirred in 100 ml of MeOH for 12 under H.sub.2 in the presence
of 10% Pd/C. The reaction mixture was filtered and concentrated in
vacuo to provide oily residue which was subjected to column
chromatography (50% Hexane/EtOAc) to provide 1.2 g (7.0 mmol) of
1-propyl-5-aminobenzimidazole and 1.1 g (6.4 mmol) of
3-propyl-5-aminobenzimidazole.
[0067] 1-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole. Reaction
of 1-propyl-5-aminobenzimidazole (1.2 g, 7.0 mmol) and ISA (2.2 g,
16 mmol) provided 1.6 g (6.6 mmol, 94%) of the expected product
after column chromatographic separation. The product obtained was
converted to the fumarate salt and recrystallized from MeOH to
afford 2.1 g (76%) of the product as a light brown solid: mp
206-207.degree. C.; Anal. Calc. for
C.sub.13H.sub.17N.sub.5.1.5C.sub.4H.sub.4O.sub.4 requires C, 54.67;
H, 5.55; N, 16.98. Found: C, 54.60; H, 5.49; N, 17.16.
EXAMPLE 14
1-Propyl-4-bromo-5-(imidazolin-2-ylamino)benzimidazole (#14)
[0068] 1-Propyl-4-bromo-5-aminobenzimidazole. To a solution of
1-propyl-5-aminobenzimidazole (1.2 g, 7.1 mmol) in 10 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 0.83 g (3.4
mmol, 48%) of the product.
[0069] 1-Propyl-4-bromo-5-(imidazoline-2-ylamino)benzimidazole. A
reaction of the amine (0.83 g, 3.4 mmol) and ISA (1.3 g, 9.7 mmol)
produced 0.44 g (1.3 mmol, 38%) of the product after
chromatographic separation. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.32 g (25%) of the product as a light brown solid: mp
206-207.degree. C.; Anal. Calc. for C.sub.13H.sub.16N.sub.5Br.0-
.5C.sub.4H.sub.4O.sub.4.0.5H.sub.2O requires C, 46.29; H, 4.92; N,
17.99. Found: C, 46.66; H, 4.86; N, 17.60.
EXAMPLE 15
3-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole. (#15)
[0070] A reaction of 3-propyl-5-aminobenzimidazole (1.0 g, 5.8
mmol) and ISA (1.9 g, 14 mmol) provided 1.3 g (5.0 mmol, 87%) of
product after column chromatography. The product obtained was
converted to the fumarate salt and recrystallized from isopropanol
to afford 0.32 g (25%) of the product as a white solid: mp
198-199.degree. C.; Anal. Calc. for
C.sub.13H.sub.17N.sub.5.1.0OC.sub.4H.sub.4O.sub.4 requires C,
56.82; H, 5.89; N, 19.49. Found: C, 57.12; H, 5.91; N, 19.61.
EXAMPLE 16
3-Propyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#16)
[0071] 3-Propyl-4-bromo-5-aminobenzimidazole. To a solution of
3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 0.40 g (1.6
mmol, 37%) of the product.
[0072] 3-Propyl-4-bromo-5- (2-imidazolin-2-ylamino)benzimidazole. A
reaction of 3-propyl-4-bromo-5-aminobenzimidazole; (0.40 g, 1.6
mmol) and ISA (0.7 g, 5.2 mmol) provided 0.32 g (1.3 mmol, 81%) of
product after column chromatography. The product obtained was
converted to the fumarate salt and-recrystallized from isopropanol
to afford 0.30 g (58%) of the product as a white solid: mp
179-181.degree. C.; Anal. Calc. for
C.sub.13H.sub.16N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
46.59; H, 4.60; N, 15.98. Found: C, 46.36; H, 4.49; N, 15.81.
EXAMPLE 17
1-Isopropyl-5-(2-imidazolin-2-ylamino)benzimidazole (#17)
[0073] 1- and 3-Isopropyl-5-aminobenzimidazole. A reaction of
5-nitrobenzimidazole (4.8 g, 29 mmol) and isopropyl bromide (3.7
ml) in a procedure described in Example 9 produces 5.1 g (23 mmol,
81%) of a mixture of 1- and 3-isopropyl-5-nitrobenzimidazole, which
was converted to the corresponding amines in hydrogenation
(H.sub.2/Pd-C). The amine mixture was subjected to column
chromatography (10% i-PrOH/CH.sub.2Cl.sub.2) to provide 1.5 g (7.9
mmol, 27%) of 1-isopropyl-5-aminobenzimidazole and 2.4 g (12.6
mmol, 44%) of 3-isopropyl-5-aminobenzimidazole.
[0074] 1-Isopropyl-5-(2-imidazolin-2-ylamino)benzimidazole.
Reaction of 1-isopropyl-5-aminobenzimidazole (0.41 g, 2.3 mmol) and
ISA (0.70 g, 5.2 mmol) provided 0.37 g (1.5 mmol, 66%) of the
expected product after column chromatographic separation. The
product obtained was converted to the fumarate salt and
recrystallized from isopropanol to afford 0.27 g (24%) of the
product as a light brown solid: mp 185-186.degree. C.; Anal. Calc.
for C.sub.13H.sub.17N.sub.5.2.0C.sub.4H.sub.4C.sub.4 requires C,
52.83; H, 5.70; N,14.67. Found: C, 53.32; H, 5.63; N, 14.97.
EXAMPLE 18
1-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#18)
[0075] 1-Isopropyl-4-bromo-5-aminobenzimidazole. To a solution of
1-isopropyl-5-aminobenzimidazole (2.4 g, 14 mmol) in 20 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 1.2 g (4.5
mmol, 35%) of the product.
[0076] 1-Isopropyl-4-bromo-5 (2-imidazolin-2-ylamino)benzimidazole.
A reaction of the amine (0.86 g, 3.4 mmol) and ISA (0.90 g, 6.7
mmol) produced 0.67 g (2.1 mmol, 61%) of the product after
chromatographic separation. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.55 g (37%) of the product as a light brown solid: mp
187-188.degree. C.; Anal. Calc. for
C.sub.13H.sub.16N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
46.59; H, 4.60; N, 15.98. Found: C, 46.35; H, 4.49; N, 15.82.
EXAMPLE 19
1-Isopropyl-4-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole
(#19)
[0077] 1-Isopropyl-4-iodo-5-aminobenzimidazole. To a solution of
1-isopropyl-5-aminobenzimidazole (0.70 g, 3.7 mmol) and
Hg(OAc).sub.2 (2.1 g, 5.6 mmol) in 10 ml of AcOH was added solution
of 12 in AcOH until it produces a precipitation: The reaction
mixture was concentrated in vacuo to provide a brown solid which
was subjected to column chromatography (5% NH.sub.3 sat'd
MeOH/CH.sub.2Cl.sub.2) to provide 0.40 g (1.3 mmol, 35%) of the
product.
[0078] 1-Isopropyl-4-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of the amine (0.40 g, 1.3 mmol) and ISA (0.5 g, 3.7
mmol) produced 0.18 g (0.48 mmol, 37%) of the product after
chromatographic separation. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.22 g (35%) of the product as a white solid: mp 208-209.degree.
C.; Anal. Calc. for
C.sub.13H.sub.16N.sub.5I.1.0C.sub.4H.sub.4O.sub.4 requires C,
42.08; H, 4.15; N, 14.43. Found: C, 41.86; H, 4.08; N, 14.17.
EXAMPLE 20
3-Isopropyl-5-(2-imidazolin-2-ylamino)benzimidazole. (#20).
[0079] A reaction of 3-isopropyl-5-aminobenzimidazole (1.0 g, 5.8
mmol) and ISA (1.5 g, 11 mmol) yielded 0.90 g (3.8 mmol, 65%) of
product after column chromatography. The product obtained was
converted to the fumarate salt and recrystallized from isopropanol
to afford 0.32 g (25%) of the product as a light brown solid: mp
206-207.degree. C.; Anal. Calc. for
C.sub.13H.sub.17N.sub.50.5C.sub.4H.sub.4O.sub.4 requires C, 54.67;
H, 5.55; N, 16.78. Found: C, 53.33; H, 5.50; N, 16.30.
EXAMPLE 21
3-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#21)
[0080] 3-Isopropyl-4-bromo-5-aminobenzimidazole. To a solution of
3-isopropyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 1.1 g (4.0
mmol, 47%) of the product.
[0081] 3-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of 3-isopropyl-4-bromo-5-aminobenzimidazole (1.1 g, 4.0
mmol) and ISA (1.2 g, 9.0 mmol) provided 0.60 g (1.9 mmol, 43%) of
product after column chromatography. The product obtained was
converted to the fumarate salt and recrystallized from EtOH to
afford 0.52 g (28%) of the product as a white crystal: mp
210-212.degree. C.; Anal. Calc. for
C.sub.13H.sub.16N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
46.59; H, 4.60; N, 15.98. Found: C, 46.60; H, 4.49; N, 15.74.
EXAMPLE 22
1-Isobutyl-5-(2-imidazolin-2-ylamino)benzimidazole (#22)
[0082] 1- and 3-Isobutyl-5-aminobenzimidazole. A reaction of
5-nitrobenzimidazole (4.8 g, 29 mmol) and isobutyl bromide (7.7 ml,
72 mmol) in a procedure described in Example 9 produces 5.3 g (24
mmol, 83%) of a mixture of 1- and 3-isopropyl-5-nitrobenzimidazole,
which was converted to the corresponding amines in hydrogenation
(H.sub.2/Pd-C). The amine mixture was subjected to column
chromatography (10% i-PrOH/CH.sub.2Cl.sub.2) to provide 1.8 g (9.4
mmol, 32%) of 1-isobutyl-5-aminobenzimidazole and 2.7 g (14 mmol,
49%) of 3-isobutyl-5-aminobenzimidazole.
[0083] 1-Isobutyl-5-(2-imidazolin-2-ylamino)benzimidazole. Reaction
of 1-isobutyl-5-aminobenzimidazole (0.29 g, 1.2 mmol) and ISA (0.6
g, 4.5 mmol) provided 0.37 g (1.2 mmol, >95%) of the expected
product after column chromatographic separation. The product
obtained was converted to the fumarate salt and recrystallized from
isopropanol to afford 0.41 g (70%) of the product as a white solid:
mp 185-186.degree. C.; Anal. Calc. for C.sub.14H.sub.19N.sub.5.
2.0C.sub.4H.sub.4O.sub.4 requires C, 53.98; H, 5.56; N, 14.31.
Found: C, 53.85; H, 5.69; N, 14.22.
EXAMPLE 23
1-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#23)
[0084] 1-Isobutyl-4-bromo-5-aminobenzimidazole. To a solution of
1-isobutyl-5-aminobenzimidazole (2.4 g, 13 mmol) in 20 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 1.2 g (4.5
mmol, 35%) of the product.
[0085] 1-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of bromoamine (0.30 g, 1.1 mmol) and ISA (0.9 g, 6.7
mmol) produced 0.28 g (0.81 mmol, 73%) of the product after
chromatographic separation. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.28 g (56%) of the product as a white solid: mp 226-227.degree.
C.
EXAMPLE 24
3-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#24)
[0086] 3-Isobutyl-4-bromo-5-aminobenzimidazole. To a solution of
3-isobutyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 1.0 g (3.7
mmol, 29%) of the product.
[0087] 3-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of 3-isobutyl-4-bromo-5-aminobenzimidazole (0.30 g, 1.1
mmol) and ISA (0.70 g, 5.2 mmol) provided 0.20 g (0.56 mmol, 51%)
of the product after column chromatography. The product obtained
was converted to the fumarate salt and recrystallized from
isopropanol to afford 0.22 g (45%) of the product as a white solid:
mp 187-188.degree. C.; Anal. Calc. for
C.sub.14H.sub.18N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
47.80; H, 4.90; N, 15.48. Found: C, 47.57; H. 4.61; N, 15.38.
EXAMPLE 25
1-Cyclopentyl-5-(2-imidazolin-2-ylamino)benzimidazole (#25)
[0088] 1- and 3-Cyclopentyl-5-aminobenzimidazole. A reaction of
5-nitrobenzimidazole (3.1 g, 19 mmol) and cyclopentyl bromide (3.8
ml, 38 mmol) in a procedure described in Example 9 produces 2.6 g
(11 mmol, 59%) of a mixture of 1- and
3-cyclopentyl-5-nitrobenzimidazole, which was converted to the
corresponding amines in hydrogenation (H.sub.2/Pd-C). The amine
mixture was subjected to column chromatography (10%
i-PrOH/CH.sub.2Cl.sub.2) to provide 1.0 g (5.0 mmol, 45%) of
1-cyclopentyl-5-aminobenzimidazole and 1.1 g (5.4 mmol, 50%) of
3-cyclopentyl-5-aminobenzimidazole.
[0089] 1-Cyclopentyl-5-(2-imidazolin-2-ylamino)benzimidazole. A
reaction of 1-cyclopentyl-5-aminobenzimidazole (0.66 g, 3.3 mmol)
and ISA (1.3 g, 9.7 mmol) provided 0.91 g (2.7 mmol, 81%) of the
expected product after column chromatographic separation. The
product obtained was converted to the fumarate salt and
recrystallized from isopropanol to afford 1.1 g (77%) of the
product as a white crystal: mp 214-215.degree. C.; Anal. Calc. for
C.sub.15H.sub.13N.sub.5.1.5C.sub.4H.sub.4O.sub.4 requires C, 56.88;
H, 5.68; N, 15.79. Found: C, 56.69; H, 5.54; N, 16.02.
EXAMPLE 26
1-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#26)
[0090] 1-Cyclopentyl-4-bromo-5-aminobenzimidazole. To a solution of
1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in 20 ml of
AcOH was added solution of Br.sub.2 in. AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 0.54 g (1.9
mmol, 35%) of the product.
[0091]
1-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A
reaction of the amine (0.54 g, 1.9 mmol) and ISA (0.74 g, 5.5 mmol)
produced 0.45 g (1.3 mmol, 67%) of the product after
chromatographic separation. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.32 g (19%) of the product as a light brown solid: mp
180-182.degree. C.; Anal. Calc. for
C.sub.15H.sub.18N.sub.5Br.1.5C.sub.4H.sub.4O.sub.4 requires C,
48.29; H, 4.63; N, 13.41. Found: C, 48.56; H, 4.54; N, 13.23.
EXAMPLE 27
3-Cyclopentyl-5-(2-imidazolin-2-ylamino)benzimidazole (#27).
[0092] A reaction of 3-cyclopentyl-5-aminobenzimidazole (0.41 g,
2.0 mmol) and ISA (0.68 g, 5.1 mmol) yielded 0.34 g (1.2 mmol, 62%)
of product after column chromatography. The product obtained was
converted to the fumarate salt and recrystallized from isopropanol
to afford 0.28 g (31%) of the product as a white solid: mp
158-159.degree. C.; Anal. Calc. for
C.sub.15H.sub.19N.sub.5.1.0C.sub.4H.sub.4O.sub.4 requires C, 56.88;
H, 5.68; N, 15.79. Found: C, 55.69; H, 5.62; N, 15.73.
EXAMPLE 28
3-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#28)
[0093] 3- Cyclopentyl-4-bromo-5-aminobenzimidazole. To a solution
of 3-cyclopentyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 20 ml of
AcOH was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide 0.70 g (2.5
mmol, 50%) of the product.
[0094]
3-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A
reaction of 3-cyclopentyl-4-bromo-5-aminobenzimidazole (0.70 g, 2.5
mmol) and ISA (0.94 g, 7.0 mmol) provided 0.26 g (0.78 mmol, 31%)
of product after column chromatography. The product obtained was
converted to the fumarate salt and recrystallized from isopropanol
to afford 0.31 g (27%) of the product as a white solid: mp
208-210.degree. C.; Anal. Calc. for
C.sub.15H.sub.18N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
49.15; H, 4.78; N, 15.08. Found: C, 49.46; H, 4.88; N, 15.38.
EXAMPLE 29
1-Cyclohexylmethyl-5-(2-imidazolin-2-ylamino)benzimidazole
(#29)
[0095] 1- and 3-Cyclohexylmethyl-5-aminobenzimidazole. A reaction
of 5-nitrobenzimidazole (3.1 g, 19 mmol) and cyclohexylmethyl
bromide (6.7 ml, 47 mmol) in a procedure described in Example 9
produces 5.0 g (19 mmol, 100%) of a mixture of 1- and
3-cyclohexylmethyl-5-nitrobenzimidazol- e, which was converted to
the corresponding amines in hydrogenation (H.sub.2/Pd-C) The amine
mixture was subjected to column chromatography (100-30%
hexane/EtOAc) to provide 2.0 g (8.7 mmol, 45%) of
1-cyclohexylmethyl-5-aminobenzimidazole and 2.5 g (11 mmol, 54%) of
3-cyclohexylmethyl-5-aminobenzimidazole.
[0096] 1-Cyclohexylmethyl-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of 1-cyclohexylmethyl-5-aminobenzimidazole (2.2 g, 9.6
mmol) and ISA (3.6 g) provided 1.8 g (8.1 mmol, 84%) of the
expected product after column chromatographic separation. The
product obtained was converted to the fumarate salt and
recrystallized from isopropanol to afford 1.9 g (4.6 mmol, 48%) of
the product as a white solid: mp 222-223.degree. C.; Anal. Calc.
for C.sub.17H.sub.23N.sub.5.1.0C.sub.4H.sub.4O.sub.4 requires C,
61.00; H, 6.58; N, 16.94. Found: C, 61.48; H, 6.41; N, 16.36.
EXAMPLE 30
1-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#30)
[0097] 1-Cyclohexylmethyl-4-bromo-5-aminobenzimidazole. To a
solution of 1-cyclohexylmethyl-5-aminobenzimidazole (2.5 g, 11
mmol) in 20 ml of AcOH was added solution of Br.sub.2 in AcOH until
it produces a precipitation. The reaction mixture was concentrated
in vacuo to provide a brown solid which was subjected to column
chromatography (5% NH.sub.3 sat'd MeOH/CH.sub.2Cl.sub.2) to provide
1.37 g (4.3 mmol, 40%) of the product.
[0098]
1-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of the amine (1.4 g, 4.4 mmol) and ISA (1.8 g, 13 mmol)
produced 1.6 g (4.1 mmol, 94%) of the product after chromatographic
separation. The product obtained was converted to the fumarate salt
and recrystallized from isopropanol to afford 1.8 g (83%) of the
product as a white solid: mp 193-195.degree. C.; Anal. Calc. for
C.sub.17H.sub.22N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
51.23; H, 5.32; N. 14.22. Found: C, 50.21; H, 5.17; N, 14.29.
EXAMPLE 31
3-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#31)
[0099] 3-Cyclohexylmethyl-4-bromo-5-aminobenzimidazole. To a
solution of 3-cyclohexylmethyl-5-aminobenzimidazole (2.0 g, 8.7
mmol) in 40 ml of AcOH was added solution of Br.sub.2 in AcOH until
it produces a precipitation. The reaction mixture was concentrated
in vacuo to provide a brown solid which was subjected to column
chromatography (5% NH.sub.3 sat'd MeOH/CHCl.sub.3) to provide 1.2 g
(3.8 mmol, 48%) of the product.
[0100]
3-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of 3-cyclohexylmethyl-4-bromo-5-aminobenzimidazole (1.2
g, 3.9 mmol) and ISA (1.5 g, 11 mmol) provided 0.85 g (2.3 mmol,
58%) of product after column chromatography. The product obtained
was converted to the fumarate salt and recrystallized from
isopropanol to afford 1.1 g (51%) of the product as a white solid:
mp 153-155.degree. C.; Anal. Calc. for
C.sub.17H.sub.22N.sub.5Br.1.5C.sub.4H.sub.4O.sub.4.0.5H.sub.2O
requires C, 49.38; H, 5.22; N, 12.58. Found: C, 49.22; H, 5.07; N,
12.19.
EXAMPLE 32
1-Benzyl-5-(2-imidazolin-2-ylamino)benzimidazole (#32)
[0101] 1- and 3-Benzyl-5-aminobenzimidazole. A reaction of
5-nitrobenzimidazole (3.0 g, 18 mmol) and benzyl bromide (4.4 ml,
37 mmol) in a procedure described in Example 9 produces 3.2 g (13
mmol, 71%) of a mixture of 1- and 3-benzyl-5-nitrobenzimidazole,
which was converted to the corresponding amines in hydrogenation
(H.sub.2/Pd-C). The amine mixture was subjected to column
chromatography (10%-30% Hexane/EtOAc) to provide 1.6 g (7.2 mmol,
55%) of 1-benzyl-5-aminobenzimidazole and 1.2 g (5.3 mmol, 41%) of
3-benzyl-5-aminobenzimidazole.
[0102] 1-Benzyl-5-(2-imidazolin-2-ylamino)benzimidazole. A reaction
of 1-benzyl-5-aminobenzimidazole (0.35 g, 1.2 mmol) and ISA (0.42
g, 3.1 mmol) provided 0.17 g (0.46 mmol, 38%) of the expected
product after column chromatographic separation. The product
obtained was converted to the fumarate salt and recrystallized from
isopropanol to afford 0.11 g (20%) of the product as a white solid:
mp 174-175.degree. C.; Anal. Calc. for
C.sub.17H.sub.17N.sub.5.1.5C.sub.4H.sub.4O.sub.4 requires C, 59.35;
H, 4.98; N, 45.05. Found: C, 59.40; H, 4.81; N, 14.99.
EXAMPLE 33
1-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#33)
[0103] 1-Benzyl-4-bromo-5-aminobenzimidazole. To a solution of
1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitate. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CHCl.sub.3) to provide 0.90 g (2.5 mmol,
60%) of the product.
[0104] 1-Benzyl-4-bromo-5-(2- imidazolin-2-ylamino)benzimidazole. A
reaction of bromoamine,(0.90 g, 3.0 mmol) and ISA (1.2 g, 8.9 mmol)
produced 0.85 g (2.3 mmol, 77%) of the product after
chromatographic separation. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford 1.1
g (70%) of the product as a white solid: mp 197-198.degree. C.;
Anal. Calc. for C.sub.17H.sub.16N.sub.5Br.1.5C.sub.4H.sub.4O.sub.4
requires C, 50.75; H, 4.07; N, 12.87. Found: C, 50.91; H, 3.87; N,
12.77.
EXAMPLE 34
3-Benzyl-5-(2-imidazolin-2-ylamino)benzimidazole (#34).
[0105] A reaction of 3-benzyl-5-aminobenzimidazole (0.34 g, 1.6
mmol) and ISA (0.68 g, 5.1 mmol) yielded 0.43 g (1.3 mmol, 76%) of
product after column chromatography. The product obtained was
converted to the fumarate salt and recrystallized from isopropanol
to afford 0.32 g (41%) of the product as a white solid: mp
174-175.degree. C.; Anal. Calc. for
C.sub.17H.sub.17N.sub.5.1.5C.sub.4H.sub.4O.sub.4 requires C, 59.35;
H, 4.98; N, 15.05. Found: C, 58.88; H, 5.19; N, 15.25.
EXAMPLE 35
3-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#35)
[0106] 3-Benzyl-4-bromo-5-aminobenzimidazole. To a solution of
3-benzyl-5-aminobenzimidazole (0.88 g, 3.9 mmol) in 20 ml of AcOH
was added solution of Br.sub.2 in AcOH until it produces a
precipitation. The reaction mixture was concentrated in vacuo to
provide a brown solid which was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/CHCl.sub.3) to provide 0.35 g (1.2 mmol,
29%) of the product.
[0107] 3-Benzyl-4-bromo-5-(2- imidazolin-2-ylamino)benzimidazole. A
reaction of 3-benzyl-4-bromo-5-aminobenzimidazole (0.35 g, 1.2
mmol) and ISA (0.43 g, 3.2 mmol) provided 0.17 g (0.46 mmol, 38%)
of the product after column chromatography. The product obtained
was converted to the fumarate salt and recrystallized from MeOH to
afford 0.12 g (21%) of the product as a white solid: mp
203-205.degree. C.; Anal. Calc. for
C.sub.17H.sub.16N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
51.87; H, 4.64; N, 14.39. Found: C, 52.60; H, 4.73; N, 14.39.
EXAMPLE 36
1-(4-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#36)
[0108] 1-(4-Methoxybenzyl)-5-aminobenzimidazole. A reaction of
5-nitrobenzimidazole (4.3 g, 27 mmol) and 4-methoxybenzyl chloride
(4.3 ml, 30 mmol) in a procedure described in Example 9 produces
5.6 g (19 mmol, 73%) of a mixture of 1- and
3-(4-methoxybenzyl)-5-nitrobenzimidazol- e, which was converted to
the corresponding amines in hydrogenation (H.sub.2/Pd-C). The amine
mixture was subjected to column chromatography (10%-30%
i-PrOH/CH.sub.2Cl.sub.2) to provide 2.1 g (8.2 mmol, 43%) of
1-(4-methoxybenzyl)-5-aminobenzimidazole and 2.4 g (9.2 mmol, 48%)
of 3-(4-methoxybenzyl)-5-aminobenzimidazole.
[0109] 1-(4-Methoxybenzyl)-4-bromo-5-aminobenzimidazole. To a
solution of 1-(4-methoxybenzyl)-5-aminobenzimidazole (0.80 g, 2.2
mmol) in 20 ml of AcOH was added solution of Br.sub.2 in AcOH until
it produces a precipitation. The reaction mixture was concentrated
in vacuo to provide a brown solid which was subjected to column
chromatography (5% NH.sub.3 sat'd MeOH/CHCl.sub.3) to provide 0.90
g (2.1 mmol, 95%) of the product.
[0110]
1-(4-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole-
. A reaction of the bromoamine (0.90 g, 2.1 mmol) and ISA (1.3 g,
9.7 mmol) provided 1.0 g (2.0 mmol, 96%) of the product after
column chromatography.
EXAMPLE 37
1-(3-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#37)
[0111] 1-(3-Methoxybenzyl)-5-aminobenzimidazole. A reaction of
5-nitrobenzimidazole (2.5 g, 15 mmol) and 3-methoxybenzyl chloride
(2.6 ml, 17 mmol) in a procedure described in Example 9 produces
1.0 g (3.1 mmol, 26%) of a mixture of 1- and
3-(3-methoxybenzyl)-S-nitrobenzimidazol- e, which was converted to
the corresponding amines in hydrogenation (H.sub.2/Pd-C). The amine
mixture was subjected to column chromatography (10%-30%
isopropanol/CH.sub.2Cl.sub.2) to provide 0.32 g (1.1 mmol, 36%) of
3-(3-methoxybenzyl)-5-aminobenzimidazole and 0.37 g (1.3 mmol, 41%)
of 1-(3-methoxybenzyl)-5-aminobenzimidazole.
[0112] 1-(3-Methoxybenzyl)-4-bromo-5-aminobenzimidazole. To a
solution of 1-(3-methoxybenzyl)-5-aminobenzimidazole (0.37 g, 1.3
mmol) in 10 ml of AcOH was added solution of Br.sub.2 in AcOH until
it produces a precipitation. The reaction mixture was concentrated
in vacuo to provide a brown solid which was subjected to column
chromatography (5% NH.sub.3 sat'd Isopropanol/CHCl.sub.3) to
provide 0.31 g (1.0 mmol, 66%) of the product.
[0113]
1-(3-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole-
. A reaction of the bromoamine (0.31 g, 0.84 mmol) and ISA (0.52 g,
3.9 mmol) provided 0.37 g (>95%) of product after column
chromatography. The product obtained was converted to the fumarate
salt and recrystallized from isopropanol to afford 0.36 g (83%) of
the product as a white crystal: mp 177-178.degree. C.; Anal. Calc.
for C.sub.18H.sub.18N.sub.5Br0.1C.sub.4H.sub.4O.sub.4.H.sub.2O
requires C, 48.63; H, 4.64; N, 12.89. Found: C, 48.06; H, 4.51; N,
12.77.
EXAMPLE 38
1-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#38)
[0114] 1- and 3-(2-Hydroxyethyl)-4-bromo-5-aminobenzimidazole. A
reaction of 5-nitrobenzimidazole (3.3 g, 20 mmol) and
2-hydroxyethyl bromide (2.2 ml, 31 mmol) in a procedure described
in Example 9 produces a mixture of 1- and
3-(2-Hydroxyethyl)-5-nitrobenzimidazole, which was converted to the
corresponding amines in hydrogenation (H.sub.2/Pd-C). The amine
mixture (3.4 g, 19 mmol) in 50 ml of AcOH was added solution of
Br.sub.2 in AcOH until it produces a precipitation. The reaction
mixture was concentrated in vacuo to provide a brown solid which
was subjected to column chromatography (5% NH.sub.3 sat'd
isopropanol/CHCl.sub.3) to provide 0.42 g (1.6 mmol) of
3-(2-hydroxyethyl)-4-bromo-5-aminobenzimidaz- ole and 0.57 g (2.2
mmol, 11%) of 1-(2-hydroxyethyl-4-bromo-5-aminobenzimi- dazole.
[0115]
1-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of 1-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole (0.25
g, 1.4 mmol) and ISA (0.35 g, 2.6 mmol) provided 0.21 g (0.87 mmol,
62%) of product after column chromatography. The product obtained
was converted to the fumarate salt and recrystallized from
isopropanol to afford 0.17 g (28%) of the product as a white solid:
mp 141-143.degree. C.; Anal. Calc. for
C.sub.12H.sub.14N.sub.5OBr.1.0C.sub.4H.sub.4O.sub.4 requires C,
43.55; H, 4.12; N, 15.87. Found: C, 44.14; H, 4.03; N, 15.53.
EXAMPLE 39
3-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#39).
[0116] A reaction of
3-(2-hydroxy-1-ethyl)-4-bromo-5-aminobenzimidazole (0.31 g, 1.8
mmol) and ISA (0.52 g, 3.9 mmol) provided 0.37 g (1.6 mmol, 88%) of
the desired product after column chromatography. The product
obtained was converted to the fumarate salt and recrystallized from
isopropanol to afford 0.32 g (40%) of the product as a white solid:
mp 217-218.degree. C.
EXAMPLE 40
1-(2-Aminoethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#40).
[0117] To a solution of 1-(2-hydroxyethyl)-5-nitrobenzimidazole
(0.27 g, 1.3 mmol) was added triphenylphosphine (0.38 g, 1.4 mmol),
DEAD (0.25 ml, 1.4 mmol) and phthalimide (0.21 g, 1.4 mmol) in a
portion and resulting mixture was stirred for 1 h at 25.degree. C.
The reaction mixture was concentrated in vacuo, yielding an oil
which was subjected to column chromatography (40% Hexane/EtOAc) to
provide 0.36 g (1.1 mmol, 82%) of
1-(2-phthalimidylethyl)-5-nitrobenzimidazole. The
nitrobenzimidazole was subsequently subjected to hydrogenation,
bromination and coupling with ISA to produce 0.41 g of
1-(2-phthalimidylethyl)-4-bromo-5-(2-imidazolin--
2-ylamino)benzimidazole which was refluxed with 0.3 ml of hydrazine
in 20 ml of MeOH for 0.5 h to yield the desired product (0.31 g,
0.96 mmol, 68% overall). The product obtained was converted to the
fumarate salt and recrystallized from isopropanol to afford 0.21 g
(24%) of the product as a white foamy solid.
EXAMPLE 41
2-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#41)
[0118] 2-Methyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenediamine (1.0 g, 6.5 mmol) in 20 ml of AcOH was
stirred at reflux for 12 h. Reaction mixture was concentrated in
vacuo to yield a dark brown residue, which, in spectroscopic
analysis, corresponds to 2-methyl-5-nitrobenzimidazole and was
subjected to a following reaction without further purification. The
nitrobenzimidazole and 50 mg of 10% Pd/C were dissolved in 100 ml
of MeOH and stirred for 12 h under H.sub.2. The reaction mixture
was filtered and concentrated in vacuo yielding 0.95 g (6.5 mmol,
>95%) of brown oil which was identified as
2-methyl-5-aminobenzimidazole in NMR and used in a following
reaction without further purification.
[0119] 2-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution
of the amine (0.70 g, 4.7 mmol) and ISA (0.8 g, 5.9 mmol) was
stirred at reflux for 12 h. The reaction mixture was concentrated
in vacuo to yield an oily residue which was subjected to silica gel
column chromatography (NH.sub.3 sat'd 20% MeOH/EtOAc) to yield 0.81
g (3.8 mmol, 81%) of the desired product.
EXAMPLE 42
2-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#42)
[0120] 2-Methyl-4-bromo-5-aminobenzimidazole. To a solution of 0.9
g (6.1 mmol) of 2-methyl-5-aminobenzimidazole in 50 ml of AcOH was
added 0.16 ml of Br.sub.2 (3.1 mmol) dropwise and resulting
reaction mixture was stirred for 1 h at 25.degree. C. Reaction
mixture was concentrated in vacuo and purified on silica gel column
chromatography (20% Isopropanol/EtOAC) to yield 0.56 g (2.5 mmol,
41%) of the desired product.
[0121] 2-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
The amine (0.56 g, 2.5 mmol) and ISA (1.0 g, 7.4 mmol) were
dissolved in 5 ml of isobutanol and stirred at reflux for 12 h. The
reaction mixture was concentrated in vacuo and subjected to column
chromatography (NH.sub.3 sat'd 20% Isopropanol/EtOAC) to yield 0.72
g (2.4 mmol, >99%) of the product. The product obtained was
converted to the fumarate salt and recrystallized from MeOH to
afford 0.25 g (25%) of the product as a white crystal: mp
222-224.degree. C.; Anal. Calc. for C.sub.11H.sub.12N.sub.5Br-
.1.0C.sub.4H.sub.4O.sub.4.0.5H.sub.2O requires C, 42.98; H, 4.09;
N, 16.71. Found: C, 43.14; H, 4.03; N, 16.33.
EXAMPLE 43
2-Ethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#43)
[0122] 2-Ethyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenedi- amine (1.0 g, 6.5 mmol) in 20 ml of
propionic acid was stirred at reflux for 12 h. Reaction mixture was
concentrated in vacuo to yield a dark brown residue, which, in
spectroscopic analysis, corresponds to 2-ethyl-5-nitrobenzimidazole
and was subjected to a following reaction without further
purification. The nitrobenzimidazole and 50 mg of 10% Pd-C were
dissolved in 100 ml of MeOH and stirred for 12 h under H.sub.2. The
reaction mixture was filtered and concentrated in vacuo yielding
0.95 g (6.5 mmol, >95%) of brown oil which was identified as
2-ethyl-5-aminobenzimidazole in NMR and used in a following
reaction without further purification.
[0123] 2-Ethyl-4-bromo-5-aminobenzimidazole. To a solution of 1.3 g
(7.7 mmol) of 2-ethyl-5-aminobenzimidazole in 50 ml of AcOH was
added 0.40 ml of Br.sub.2 (7.5 mmol) dropwise and resulting
reaction mixture was stirred for 1 h at 25.degree. C. The reaction
mixture was concentrated in vacuo and purified on silica gel column
chromatography (20% isopropanol /EtOAC) to yield 1.5 g (6.3 mmol,
82%) of the desired product.
[0124] 2-Ethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A
reaction of 2-ethyl-4-bromo-5-aminobenzimidazole (1.5 g, 6.3 mmol)
with ISA (2.3 g, 17 mmol) provides 1.4 g (4.5 mmol, 71%) of the
desired product. The product obtained was converted to the fumarate
salt and recrystallized from isopropanol to afford 1.53 g (61%) of
the product as a white solid: mp 186-187.degree. C.; Anal. Calc.
for C.sub.12H.sub.14N.sub.5Br.1.0C.sub- .4H.sub.4O.sub.4 requires
C, 45.30; H, 4.28; N, 16.51. Found: C, 45.03; H, 4.11; N,
16.88.
EXAMPLE 44
2-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#44)
[0125] 2-Isopropyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml of
isobutyric acid was stirred at reflux for 12 h. The reaction
mixture was concentrated in vacuo to yield a dark brown residue,
which was dissolved in 100 ml of EtOAc and washed with aqueous
NaHCO.sub.3. Organic layer was dried over MgSO.sub.4 and
concentrated in vacuo, yielding an oil which was characterized as
2-isopropyl-5-nitrobenzimidazole and subjected to a following
reaction without further purification. The nitrobenzimidazole and
50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for
12 h under H.sub.2. The reaction mixture was filtered and
concentrated in vacuo, yielding 0.95 g (5.4 mmol, 92%) of the
desired product.
[0126] 2-Isopropyl-4-bromo-5-aminobenzimidazole. To a solution of
0.95 g (5.4 mmol) of 2-isopropyl-5-aminobenzimidazole in 50 ml of
AcOH was added 0.19 ml (3.7 mmol) of Br.sub.2 dropwise and
resulting reaction mixture was stirred for 1 h at 25.degree. C.
Reaction mixture was concentrated in vacuo and purified on silica
gel column chromatography (5% MeOH/EtOAC) to yield 0.89 g (3.5
mmol, 95%) of the desired product.
[0127] 2-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
A reaction of the bromoamine (0.89 g, 3.5 mmol) and ISA (1.5 g, 11
mmol) provides 0.42 g (1.3 mmol, 37%) of the expected product. The
product obtained was converted to the fumarate salt and
recrystallized from EtOH to afford 0.43 g (28%) of the product as a
light gray solid: mp 176-178.degree. C.; Anal. Calc. for
C.sub.13H.sub.16N.sub.5Br. 1.0C.sub.4H.sub.4O.sub.4 requires C,
46.59; H, 4.60; N, 15.98. Found: C, 45.14; H, 4.39; N, 15.78
EXAMPLE 45
2-tert-Butyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#45)
[0128] 2-tert-Butyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenediamine (2.0 g, 13 mmol) in 10 ml of
trimethylacetic acid was stirred at reflux for 12 h. Reaction
mixture was concentrated in vacuo to yield a oil which was
subjected to column chromatography (CHCl.sub.3, neat) to yield 2.2
g (10 mmol, 77%) of 2-tert-butyl-5-nitrobenzimidazole. The
nitrobenzimidazole and 0.5 g of 10% Pd-C were dissolved in 100 ml
of MeOH and stirred for 12 h under H.sub.2. The reaction mixture
was filtered and concentrated in vacuo to provide 1.9 g (10 mmol,
>95%) of the desired product.
[0129] 2-tert-Butyl-4-bromo-5-aminobenzimidazole. To a solution of
0.53 g (2.8 mmol) of 2-tert-butyl-5-aminobenzimidazole in 50 ml of
AcOH was added 0.05 ml (1.0 mmol) of Br.sub.2 dropwise and
resulting reaction mixture was stirred for 1 h at 25.degree. C.
Reaction mixture was concentrated in vacuo and purified on silica
gel column chromatography (CHCl.sub.3, neat) to yield 0.18 g (0.67
mmol, 67%) of the desired product.
[0130]
2-tert-Butyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A
reaction of the bromoamine (0.18 g, 0.67 mmol) and ISA (0.30 g, 2.2
mmol) provides 0.21 g (0.62 mmol, 93%) of the product. The product
obtained was converted to the fumarate salt and recrystallized from
EtOH- to afford 0.43 g (28%) of the product as a light gray solid:
mp 176-178.degree. C.; Anal. Calc. for
C.sub.14H.sub.18N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
47.48; H, 4.90; N, 15.48. Found: C, 45.14; H, 4.39; N, 15.78.
EXAMPLE 46
2-Trifluoromethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#37)
[0131] 2-Trifluoromethyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenediamine (3.0 g, 20 mmol) in 15 ml of
trifluoroacetic acid was stirred at reflux for 12 h. The reaction
mixture was concentrated in vacuo to yield a oily residue, which
was dissolved in 100 ml of EtOAc and washed with aqueous
NaHCO.sub.3. The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to provide an oil which was characterized as
2-trifluromethyl-5-nitrobenzimidazole and subjected to the
following reaction without further purification. The
nitrobenzimidazole and 500 mg of 10% Pd-C were dissolved in 100 ml
of MeOH and stirred for 12 h under H.sub.2. The reaction mixture
was filtered and concentrated in vacuo, yielding 3.2 g (16 mmol,
80%) of the desired product.
[0132] 2-Trifluoroethyl-4-bromo-5-aminobenzimidazole. To a solution
of 3.2 g (16 mmol) of 2-trifluromethyl-5-aminobenzimidazole in 50
ml of AcOH was added 0.34 ml (6.6 mmol) of Br.sub.2 dropwise and
resulting reaction mixture was stirred for 1 h at 25.degree. C. The
reaction mixture was concentrated in vacuo and purified on silica
gel column chromatography (10% MeOH/CHCl.sub.3) to yield 1.7 g (6.2
mmol, 94%) of the desired product.
[0133]
2-Trifluoromethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
Reaction of the bromoamine (1.3 g, 4.6 mmol) and ISA (1.5 g)
provided 0.39 g (1.1 mmol, 23%) of the desired product. The product
obtained was converted to the fumarate salt and recrystallized from
EtOH to afford 0.40 g (21%) of the product as a light brown solid:
mp 231-232.degree. C.
EXAMPLE 47
2-Cyclopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#47)
[0134] 2-Cyclopropyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenediamine (1.0 g, 6.6 mmol) in 15 ml of
cyclopropanecarboxylic acid was stirred at reflux for 12 h. The
reaction mixture was concentrated in vacuo to yield a oil, which
was dissolved in 100 ml of EtOAc and washed with aqueous
NaHCO.sub.3. Organic layer was dried over MgSO.sub.4 and
concentrated in vacuo, yielding an oil which was characterized as
2-cyclopropyl-5-nitrobenzimidazole and subjected to a following
reaction without further purification. The nitrobenzimidazole and
So mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for
12 h under H.sub.2. The reaction mixture was filtered and
concentrated in vacuo to provide 0.87 g (4.9 mmol, 75%) of the
desired product.
[0135] 2-Cyclopropyl-4-bromo-5-aminobenzimidazole. To a solution of
0.87 g (4.9 mmol) of 2-cyclopropyl-5-aminobenzimidazole in 50 ml of
AcOH was added 0.10 ml (1.9 mmol) of Br.sub.2 dropwise and
resulting reaction mixture was stirred for 1 h at 25.degree. C. The
reaction mixture was concentrated in vacuo and purified on silica
gel column chromatography (5% MeOH/EtOAC) to yield 0.42 g (1.8
mmol, 95%) of the desired product.
[0136] 2 - Cyclopropyl -4-bromo-5-(2-imidazolin-
2-ylamino)benzimidazole. A reaction of the bromoamine (0.69 g, 2.4
mmol) and ISA (1.1 g, 8.2 mmol) provides 0.71 g (2.2 mmol, 92%) of
the desired product. The product obtained was converted to the
fumarate salt and recrystallized from isobutanol to afford 0.62 g
(62%) of the product as a light yellow solid: mp 81-83.degree. C.;
Anal. Calc. for C.sub.13H.sub.14N.sub.5Br.1.0C.sub.4-
H.sub.4O.sub.4.1.0H.sub.2O requires C, 44.95; H, 4.44; N, 15.42.
Found: C, 45.28; H, 4.35; N, 14.94.
EXAMPLE 48
2-Diphenylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole
(#48)
[0137] 2-Diphenylmethyl-5-aminobenzimidazole. A solution of
4-nitro-1,2-phenylenediamine (2 g, 13 mmol) in 10 g of
diphenylacetic acid(neat) was stirred at reflux for 12 h. Reaction
mixture was concentrated In Vacuo to yield a dark brown residue,
which was dissolved in 100 ml of EtOAc and washed with aqueous
NaHCO.sub.3. Organic layer was dried over MgSO.sub.4 and
concentrated in vacuo, yielding an oil which was purified on column
chromatography (50% Hexane/EtOAc) to yield 1.7 g (5.3 mmol, 39%) of
2-diphenylmethyl-5-nitrobenzimidazole. The nitrobenzimidazole and
250 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for
12 h under H.sub.2. The reaction mixture was filtered and
concentrated in vacuo to provide 1.4 g (5.2 mmol, >95%) of the
desired product.
[0138] 2-Diphenylmethyl-4-bromo-5-aminobenzimidazole. To a solution
of 1.1 g (3.7 mmol) of 2-diphenylmethyl-5-aminobenzimidazole in 50
ml of AcOH was added 0.07 ml (1.3 mmol) of Br.sub.2 dropwise and
resulting reaction mixture was stirred for 1 h at 25.degree. C.
Reaction mixture was concentrated in vacuo and purified on silica
gel column chromatography (5% MeOH/EtOAC) to yield 0.42 g (1.1
mmol, 86%) of the desired product.
[0139]
2-Diphenylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A
reaction of the amine (1.1 g, 2.9 mmol) and ISA (1.5 g, 11 mmol)
produces 0.51 g ( 1.1 mmol, 39%) of the expected product. The
product obtained was converted to the fumarate salt and
recrystallized from MeOH to afford 0.31 g (21%) of the product as a
light brown solid: mp 240-242.degree. C.; Anal. Calc. for
C.sub.23H.sub.20N.sub.5Br.1.0C.sub.4H.sub.4O.sub.4 requires C,
57.66; H, 4.30; N, 12.45. Found: C, 57.58; H, 4.12; N, 12.28.
EXAMPLE 49
6-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#49)
[0140] 6-Methyl-5-aminobenzimidazole. To a solution of 20 ml of
fuming nitric acid was added 5-methylbenzimidazole (1.6 g, 12 mmol)
slowly over 0.5 h and reaction mixture was stirred for 3 h at
-15.degree. C. During addition of substrate, reaction temperature
was kept below -10.degree. C. Sticky reaction mixture was then
poured into ice water to form a yellow precipitation, which was
collected and dried in vacuo to provide 0.37 g (2.1 mmol, 17%) of
5-methyl-6-nitrobenzimidazole. The nitrobenzimidazole was converted
to the corresponding amine (0.32 g, 95%) on hydrogenation (H.sub.2,
Pd/C).
[0141] 6-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. The amine
obtained above was stirred at reflux with ISA (0.96 g, 7.2 mmol) in
isobutanol for 12 h. Column chromatographic separation of reaction
mixture (NH.sub.3 sat'd 30% MeOH/EtOAc) produced 0.40 g (1.6 mmol,
78%) of the desired product. The product obtained was converted to
the fumarate salt and recrystallized from EtOH to afford 0.43 g
(63%) of the product as a white solid: mp 219-221.degree. C.; Anal.
Calc. for C.sub.11H.sub.13N.sub.5.1.0C.sub.4H.sub.4O.sub.4 requires
C, 54.38; H, 5.17; N, 21.14. Found: C, 54.14; H, 5.33; N,
20.84.
EXAMPLE 50
4,6-Dibromo-5-(2-imidazolin-2-ylamino)benzimidazole (#50).
[0142] To a solution of
4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.2 g, 0.7 mmol)
in 10 ml AcOH was added 200 mg of Hg(OAc).sub.2 and few drops of
Br.sub.2. Reaction mixture was concentrated in vacuo, yielding a
dark oily residue, which was subjected to silica gel column
chromatography (NH.sub.3 sat'd 30% MeOH/EtOAc) to provide 210 mg
(0.58 mmol, 86%) of the desired product. The product obtained was
converted to the fumarate salt and recrystallized from EtOH to
afford 0.051 g (14%) of the product as a white solid.
EXAMPLE 51
7-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#51)
[0143] 2,4-Dinitro-6-bromoaniline. To a solution of
2,4-dinitroaniline (2.2 g, 12 mmol) in 40 ml of AcOH was added 1.0
ml of Br.sub.2 dropwise and reaction mixture was stirred for 1 h.
The reaction mixture was concentrated in vacuo, yielding a dark
residue which was diluted with EtOAc and washed with aqueous
NaHCO.sub.3. Organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to provide 2.9 g (11 mmol, 92%) of
2,4-dinitro-6-bromo-aniline which was characterized by NMR and used
in a following reaction without further purification.
[0144] 4-Bromo-6-aminobenzimidazole. A solution of 4.0 g of
SnCl.sub.2.2H.sub.2O and 15 ml of HCl was added into
2,4-dinitro-6-bromoaniline (1.8 g, 6.9 mmol) and resulting reaction
mixture was stirred for 2 h at 25.degree. C. The reaction mixture
was then basified by adding 15% aq. NaOH and extracted with
CHCl.sub.3 several times. Combined extracts were dried over
MgSO.sub.4 and concentrated in vacuo to produce 1.4 g (>95%) of
corresponding amine. The amine was stirred at reflux in 10 ml of
formic acid and 10 ml of acetic anhydride for 12 h. The reaction
mixture was concentrated in vacuo, yielding oily residue which was
stirred in 30 ml of HCl sat'd EtOH for 0.5 h. The oily reaction
mixture after concentration was subjected to column chromatography
(5% NH.sub.3 sat'd MeOH/EtOAc) to yield 1.3 g (>95%) of the
desired product.
[0145] 7-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole.
4-bromo-6-aminobenzimidazole (0.4 g, 1.9 mmol) and ISA (1.2 g, 8.9
mmol) was dissolved in isobutanol and stirred at reflux for 12 h.
Column chromatographic separation of the reaction mixture (NH.sub.3
sat'd 20% MeOH/EtOAc) provided 0.41 g (1.5 mmol, 78%) of the
product. The product obtained was converted to the fumarate salt
and recrystallized from isopropanol to afford 0.24 g (32%) of the
product as a light brown solid: mp 217-218.degree. C.; Anal. Calc.
for C.sub.10H.sub.10N.sub.5Br.1.0C.sub- .4H.sub.4O.sub.4 requires
C, 42.44; H, 3.56; N, 17.68. Found: C, 42.28; H, 3.58; N,
17.40.
EXAMPLE 52
7-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#52)
[0146] 4-Methyl-6-aminobenzimidazole. To the solution of
4-bromo-6-aminobenzimidazole (0.85 g, 6.0 mmol) in sealed tube with
10 ml of DMF was added tetramethyltin (1.7 ml, 12 mmol) and
bis(triphenylphosphine)palladium(II) chloride (0.20 g). The
resulting reaction mixture was stirred for 12 h at 140.degree. C.
and concentrated in vacuo, yielding oily residue which was
subjected to column chromatography (5% MeOH/CHCl.sub.3)to produce
0.28 g (45%) of the desired product.
[0147] 7-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution
of the amine (0.28 g, 1.8 mmol) and ISA (0.82 g, 6.2 mmol) was
stirred at reflux for 24 h. The reaction mixture was subjected to
column chromatography (30% NH.sub.3 sat'd MeOH/ EtOAc) to yield
0.23 g (57%) of the product. The product obtained was converted to
the fumarate salt and recrystallized from isopropanol to afford
0.24 g (40%) of the product as a light brown solid: mp
229-231.degree. C.; Anal. Calc. for
C.sub.11H.sub.13N.sub.5.1.0C.sub.4H.sub.4O.sub.4 requires C, 54.38;
H, 5.17; N, 21.14. Found: C, 54.02; H, 5.15; N, 20.48.
EXAMPLE 53
7-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole (#53)
[0148] 4-chloro-6-aminobenzimidazole. Methanolic solution of
6-chloro-2,4-dinitroaniline (2.4 g, 11 mmol) was stirred overnight
with 100 mg of 10% Pd/C under H.sub.2. Reaction mixture was
filtered and concentrated in vacuo to provide an oil which was
dissolved in 10 ml of acetic anhydride and 10 ml of formic acid and
stirred at reflux for 12 h. The reaction mixture was concentrated
in vacuo, yielding a brown oil which was characterized as
4-chloro-6-foramidylbenzimidazole in NMR analysis. The foramide was
dissolved in 20 ml of HCl sat'd EtOH and stirred for 3 h at
25.degree. C. The reaction mixture was purified in column
chromatography (5% MeOH/EtOAc) to provide 0.89 g (5.3 mmol, 48%
overall) of the desired product.
[0149] 7-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole. A solution
of 4-chloro-6-aminobenzimidazole (0.9 g, 5.4 mmol) and ISA (1.7 g,
13 mmol) was stirred at reflux for 24 h. Column chromatographic
separation of reaction mixture (30% NH.sub.3 sat'd MeOH/EtOAc)
provided 0.53 g (2.2 mmol, 41%) of the product. The product
obtained was converted to the fumarate salt and recrystallized from
MeOH to afford 0.41 g (22%) of the product as a light brown solid:
mp 220-221.degree. C.; Anal. Calc. for
C.sub.10H.sub.10N.sub.5Cl.1.0C.sub.4H.sub.4O.sub.4 requires C,
47.81; H, 4.01; N, 19.91. Found: C, 46.03; H, 4.14; N, 19.64.
EXAMPLE 54
7-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole (#54)
[0150] 2,4-Dinitro-6-iodoaniline. To a solution of
2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc).sub.2 (6.6 g, 21
mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I.sub.2 in 100
ml of AcOH dropwise and reaction mixture was stirred for 12 h. The
reaction mixture was concentrated in vacuo, yielding a dark residue
which was diluted with EtOAc and washed with aqueous NaHCO.sub.3.
Organic layer was dried over MgSO.sub.4 and concentrated in vacuo
to produce dark residue which was subjected to column
chromatography (CHCl.sub.3, neat) to provide 4.1 g (13 mmol, 81%)
of 2,4-dinitro-6-iodoaniline.
[0151] 7-Iodo-5-aminobenzimidazole. A solution of 10 g of
SnCl.sub.2.2H.sub.2O and 20 ml of HCl was added into
2,4-dinitro-6-iodoaniline (4.1 g, 13 mmol) and resulting reaction
mixture was stirred at reflux for 48 h. The reaction mixture was
then basified by adding 15% aq. NaOH and extracted with CHCl.sub.3
several times. Combined extracts were dried over MgSO.sub.4 and
concentrated in vacuo, yielding oily residue which was subjected to
column chromatography (5% MeOH/EtOAc) to yield 1.1 g (4.4 mmol,
33%) of the amine. The amine was stirred at reflux in 10 ml of
formic acid and 10 ml of acetic anhydride for 12 h. The reaction
mixture was concentrated in vacuo to yield an oily residue which
was stirred in 30 ml of HCl sat'd EtOH for 2 h. The oily reaction
mixture after concentration was subjected to column chromatography
(5% NH, sat'd MeOH/EtOAc) to provide 0.69 g (2.7 mmol,60%) of the
desired product.
[0152] 7-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole. A solution
of 4-iodo-6-aminobenzimidazole (0.69 g, 2.7 mmol) and ISA (0.90 g,
6.7 mmol) was stirred at reflux for 12 h. Column chromatographic
separation (30% NH.sub.3 sat'd MeOH/EtOAC) of resulting reaction
mixture provided 0.88 g (>99%) of the product. The product
obtained was recrystallized from isopropanol to afford 0.56 g (64%)
of the product as a light brown solid: mp 180-181.degree. C.
EXAMPLE 55
7-Ethyl-5-(2-imidazoline-2-ylamino)benzimidazole (#55)
[0153] 2,4-Diamino-6-ethylaniline. A solution of
2,4-dinitro-6-bromoanilin- e (1.6 g, 6.1 mmol), tetraethyltin (2.4
ml, 12.2 mmol) and Cl.sub.2Pd(PPh.sub.3).sub.2 (100 mg) in 10 ml of
DMF was stirred at 140.degree. C. for 12 h. Reaction mixture was
concentrated in vacuo, yielding an oil which was purified on silica
gel column chromatography (CH.sub.2Cl.sub.2, neat) to provide 0.68
g (3.2 mmol, 53%) of 2,4-dinitro-6-ethylaniline, which was
converted to the diamine (0.45 g, 95%) on hydrogenation
(H.sub.2/Pd-C).
[0154] 7-Ethyl-5-aminobenzimidazole. The amine (0.46 g, 3.1 mmol)
was stirred at reflux in formic acid for 12 h. The reaction mixture
was concentrated in vacuo to provide an oil, which was disolved in
50 ml of HCl sat'd EtOH and stirred for 1 h. The reaction mixture
was concentrated in vacuo, yielding an oil, which was subjected to
column chromatography (EtOAc, neat) to provide 0.23 g (1.5 mmol,
47%) of the desired product.
[0155] 7-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole. The
benzimidazole (0.23 g, 1.5 mmol) and ISA (0.67 g, 5.0 mmol) was
dissolved in isobutanol and stirred at reflux for 12 h. Column
chromatographic separation of reaction mixture (NH.sub.3 sat'd 20%
MeOH/EtOAc) provided 0.30 g (1.4 mmol, 92%) of the product. The
product obtained was converted to the fumarate salt and
recrystallized from isopropanol to afford 0.17 g (46%) of the
product as a light brown solid: mp 203-205.degree. C.; Anal. Calc.
for C.sub.12H.sub.15N.sub.5.1.0C.sub.4H.sub.4O.sub.4 requires C,
55.65; X, 5.55; N, 20.28. Found: C, 55.90; H, 5.43; N, 19.87.
EXAMPLE 56
7-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole (#56)
[0156] 2,4-Diamino-6-butylaniline. A solution of
2,4-dinitro-6-bromoanilin- e (2.0 g, 7.6 mmol), tetrabutyltin (5.3
ml, 15.2 mmol) and Cl.sub.2Pd(PPh.sub.3).sub.2 (100 mg) in 10 ml of
DMF was stirred at 140.degree. C. for 12 h. Reaction mixture was
concentrated in vacuo, yielding an oil which was purified on silica
gel column chromatography (CH.sub.2Cl.sub.2, neat) to provide 0.50
g (2.0 mmol, 27%) of 2,4-dinitro-6-butylaniline, which was
converted to the diamine (0.38 g, >95%) on hydrogenation
(H.sub.2/Pd-C).
[0157] 7-Butyl-5-aminobenzimidazole. The amine (0.46 g, 3.1 mmol)
was stirred at reflux in formic acid for 12 h. reaction mixture was
concentrated in vacuo to provide an oil, which was dissolved in 50
ml of HCl sat'd EtOH and stirred for 1 h. The reaction mixture was
concentrated in vacuo, yielding an oil, which was subjected to
column chromatography (EtOAc, neat) to provide 0.11 g (0.86 mmol,
28%) of the desired product.
[0158] 7-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole. The
benzimidazole (0.11 g, 0.86 mmol) and ISA (0.25 g, 1.9 mmol) was
dissolved in isobutanol and stirred at reflux for 12 h. Column
chromatographic separation of reaction mixture (NH.sub.3 sat'd 20%
MeOH/EtOAc) provided 0.21 g (0.81 mmol, 95%) of the product. The
product obtained was converted to the fumarate salt and
recrystallized from isopropanol to afford 0.17 g (45%) of the
product as a light brown solid: mp 115-117.degree. C.; Anal. Calc.
for C.sub.14H.sub.19N.sub.5.1.5C.sub.4H.s- ub.4O.sub.4 requires C,
55.68; H, 5.84; N, 16.23. Found: C, 54.90; H, 5.84; N, 15.99.
EXAMPLE 57
7-Phenyl-5-(2-imidazolin-2-ylamino)benzimidazole (#57)
[0159] 2,4-Diamino-6-phenylaniline. A solution of
2,4-dinitro-6-bromoanili- ne (2.5 g, 9.5 mmol), tetraphenylltin
(6.1 g, 14.3 mmol) and Cl.sub.2Pd(PPh.sub.3).sub.2 (100 Mg) in 10
ml of DMF was stirred at 140.degree. C. for 12 h. Reaction mixture
was concentrated in vacuo, yielding an oil which was purified on
silica gel column chromatography (CH.sub.2Cl.sub.2, neat) to
provide 1.0 g (3.8 mmol, 41%) of 2,4-dinitro-6-phenylaniline, which
was converted to the diamine (0.72 g, >95%) on hydrogenation
(H.sub.2/Pd-C).
[0160] 7-Phenyl-5-aminobenzimidazole. The amine (0.72 g, 3.8 mmol)
was stirred at reflux in formic acid for 12 h. The reaction mixture
was concentrated in vacuo to provide an oil, which was dissolved in
50 ml of HCl sat'd EtOH and stirred for 1 h. The reaction mixture
was concentrated in vacuo, yielding an oil, which was subjected to
column chromatography (EtOAc, neat) to provide 0.48 g (2.3 mmol,
60%) of the desired product.
[0161] 7-Phenyl-5-(2-imidazolin-2-ylamino)benzimidazole. The
benzimidazole (0.48 g, 2.3 mmol) and ISA (1.0 g, 7.5 mmol) was
dissolved in isobutanol and stirred at reflux for 12 h. Column
chromatographic separation of reaction mixture (NH.sub.3 sat'd 20%
MeOH/EtOAc) provided 0.64 g (0.23 mmol, >95%) of the product.
The product obtained was converted to the fumarate salt and
recrystallized from isopropanol to afford 0.25 g (24%) of the
product as a light brown solid: mp 149-151.degree. C.; Anal. Calc.
for C.sub.16H.sub.15N.sub.5.1.5C.sub.4H.sub.4O.sub.4 requires C,
58.53; H, 4.69; N, 15.51. Found: C, 57.79; H, 4.80; N, 15.31.
EXAMPLE 58
4,7-Dibromo=-5-(2- imidazolin-2-ylamino)benzimidazole (#58)
[0162] To a solution of
7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g, 2.1 mmol)
in 10 ml of AcOH was added Br.sub.2 (0.057 ml, 1.1 mmol) in a
portion. The resulting reaction mixture was stirred for 1 h at
25.degree. C. Concentration of reaction mixture in vacuo yields a
brown oil which was subjected to column chromatography (30%
NH.sub.3 sat'd MeOH/EtOAc) to provides 0.28 g (1.5 mmol, 71%) of
the desired product. The product obtained was recrystallized from
MeOH to afford 0.22 g (56%) of the product as a light brown solid:
mp 320-321.degree. C.; Anal. Calc. for
C.sub.10H.sub.9N.sub.5Br.sub.2 requires C, 33.45; H, 2.53; N,
19.51. Found: C, 33.93; H, 4.05; N, 19.01.
EXAMPLE 59
4-Bromo-7-methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#59)
[0163] 4-Bromo-7-methyl-5-aminobenzimidazole. A solution of
[0164] 4,7-dibromo-5-aminobenzimidazole (1.5 g, 5.1 mmol) in 10 ml
of DMF was transferred into pressure bottle under Ar.sub.2. To the
solution was added tetramethyltin (3.6 ml, 20 mmol). and
bis(triphenylphosphine)pallad- ium(II) chloride (200 mg). The
resulting reaction mixture was stirred at 140.degree. C. for 24 h
and concentrated in vacuo, yielding a dark oil which was subjected
to column chromatography (40% EtOAC/CHCl.sub.3) to yield 0.34 g
(1.5 mmol, 29%) of the desired product as well as 0.75 g of
4,7-dimethyl-5-aminobenzimidazole.
[0165] 4-Bromo-7-methyl-5-(2-imidazolin-2-ylamino)benzimidazoles. A
solution of the amine (0.34 g, 1.5 mmol) and ISA (0.69 g, 5.1 mmol)
in 10 ml of isobutanol was stirred at reflux for 12 h. The
resulting reaction mixture was purified on column chromatography
(30% NH.sub.3 sat'd MeOH/EtOAc) to yield 0.25 g (0.86 mmol, 57%) of
the desired product. The product obtained was recrystallized from
MeOH to afford 0.13 g (30%) of the product as a light brown solid:
mp 242-244.degree. C.; Anal. Calc. for C.sub.11H.sub.12N.sub.5Br
requires C, 44.91; H, 4.11; N, 23.81. Found: C, 43.93; H, 4.05; N,
23.01.
EXAMPLE 60
4-Bromo-7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (#60).
[0166] To a solution of
7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61 g, 2.6 mmol)
in 10 ml of AcOH was added 0.3 ml of Br.sub.2. Resulting reaction
mixture was stirred for 12 h at 25.degree. C. and concentrated in
vacuo, yielding an oil, which was subjected to column
chromatography (NH.sub.3 sat'd 30% MeOH/EtOAc) to yield 0.23 g
(0.85 mmol, 33%) of the desired product. The product obtained was
converted to the fumarate salt and recrystallized from MeOH to
afford 0.12 g (12%) of the product as a light yellow solid: mp
244-246.degree. C.; Anal. Calc. for
C.sub.10H.sub.9N.sub.5BrCl.1.0C.sub.4H.sub.4O.sub.4.0.5H.sub.2O
requires C, 37.77; H, 3.17; N,18.35. Found: C, 37.75; H, 3.08; N,
18.21.
[0167] Pharmacological Profiles of the Compounds in Cloned Human
Adrenergic Receptors.
[0168] Binding and functional assays were performed using stably
transfected human alpha adrenergic receptors. Equilibrium
competition binding assays were performed with membrane
preparations from cultured LM cells stably transfected with the
cloned human adrenoceptor subtypes except for .alpha..sub.2b, which
was expressed in Y-1 cells, using [.sup.3H]prazosin for
.alpha..sub.1 receptors and [.sup.3H]rauwolscine for .alpha..sub.2
receptors.
EXAMPLE 61
[0169] Protocol for the determination of the potency of
.alpha..sub.2 agonists
[0170] The activity of the compounds at the different receptors was
determined in vitro using cultured cell lines that selectively
express the receptor of interest. These cell lines were prepared by
transfecting the cloned cDNA or cloned genomic DNA or constructs
containing both genomic DNA and cDNA encoding the human alpha
adrenergic receptors as described below. Table 1 shows the binding
and functional activities at cloned human alpha adrenergic
receptors.
[0171] .alpha..sub.2A Sean Adrenergic Receptor: The entire coding
region of .alpha..sub.2A (1350 bp), including 1.0 kilobasepairs of
5' untranslated sequence (5'UT) and 100 bp of 3' untranslated
sequence (3'UT), was cloned into the Smal site of the eukaryotic
expression vector pCEXV-3. The insult housing this coding region
was an @2.5 kb Kpnl/HindIII human placenta genomic fragment which
was end-blunted by either T.sub.4 polymerase or Klenow fragment of
DNA polymerase. Stable cell lines were obtained by cotransfection
with the Plasmid pGCcos3neo (plasmid containing the .alpha..sub.2A
receptor gene) and the plasmid pGCcos3neo (plasmid containing the
aminoglycoside transferase gene) into LM(tk-), CHO, and NIT3T3
cells, using calcium phosphate technique. The cells were grown, in
a controlled environment (37.degree. C., 5% CO.sub.2), as
monolayers in Dulbecco's modified Eagle's Medium (GIBCO, Grand
Island, N.Y.) containing 25 mM glucose and supplemented with 10%
bovine calf serum, 100 units/ml penicillin g, and 100 .mu.g/ml
streptomycin sulfate. Stable clones were then selected for
resistance to the antibiotic G-418 (1 mg/ml), and membranes were
harvested and assayed for their ability to bind
[.sup.3H]rauwolscine as described below (see "Radioligand Binding
Assays")
[0172] .alpha..sub.2B Human Adrenergic Receptor: The entire coding
region of .alpha..sub.2B (1350 bp), including 393 bp of
5'untranslated sequence and 11 bp of 3' untranslated sequence, was
cloned into the eukaryotic expression vector pcEXV-3 (Weinshank et
al, U.S. Pat. No. 5,053,337, issued Oct. 1, 1991). Stable cell
lines were selected as described above.
[0173] .alpha..sub.2C Human Adrenergic Receptor: The entire coding
region of .alpha..sub.2C (1383 bp), including 2 bp of 5' UT and 400
bp of 3' UT, was cloned into the Smal site of the eukaryotic
expression vector pCEXV-3. The insert housing this coding region
was an @1.8 kb Ncol/EcoRI human spleen genomic fragment which was
end-blunted by either T.sub.4 polymerase or Klenow fragment of DNA
polymerase. Stable cell lines were selected as described above.
[0174] Radioligand Binding Assays: Transfected cells from culture
flasks were scraped into 5 ml of 5 mM Tris-HCl, 5 mM EDTA, pH 7.5,
and lysed by sonication. The cell lysates were centrifuged at 1000
rpm for 5 min at 4.degree. C., and the supernatant was centrifuged
at 30,000.times.g for 20 min at 4.degree. C. The pellet was
suspended in 50 mM Tris-HCl, 1 mM MgCl.sub.2, and 0.1% ascorbic
acid at pH 7.5. Binding of .alpha..sub.2 antagonist
[.sup.3H]rauwolscine (0.5 mM) to membrane preparations of LM(tk-)
cells was done in a final volume of 0.25 ml and incubated at
37.degree. C. for 20 min. Nonspecific binding was determined in the
presence of 10 .mu.M phentolamine. The reaction was stopped by
filtration through GF/B filters using a cell harvester. Inhibition
experiments, routinely consisting of 7 concentrations of the tested
compounds, were analyzed using a non-linear regression
curve-fitting computer program to obtain Ki values.
[0175] Measurement of Agonist Activity: The agonist activity
(expressed as pEC.sub.50) was measured as a function of the ability
to inhibit the forskolin-stimulated synthesis of cyclic adenosine
monophosphate (cAMP). The stably transfected cells were incubated
in Ham's F10 with 5 mM theophylline, 10 mM HEPES, 10 .mu.M
pargyline, and/or appropriate concentrations of forskolin for 20
min at 37.degree. C. in 5% CO.sub.2. The tested compounds were then
added to a final concentration of 0.001 nM to 1 .mu.M and incubated
for an additional 15 min at 37.degree. C. in 5% CO.sub.2. The
medium was aspirated and the reaction was stopped by the addition
of 100 mM HCl. To demonstrate competitive antagonism, a
dose-response curve for norepinephrine was measured in parallel,
using a fixed-dose of norepinephrine (0.32 .mu.M). The plates are
stored at 4.degree. C. for 15 min and assayed to determine the
linear concentration of cAMP. The appropriate dilution is
interpolated from the standard curve of cold cAMP. The assessment
of cAMP formation is determined by radioimmunoassay (cAMP
radioimmunoassay kit; Advanced Magnetics, Cambridge, Mass.).
Radioactivity was quantified using a Packard COBRA Auto Gamma
counter, equipped with data reduction software.
[0176] .alpha..sub.1A Human Adrenergic Receptor: The entire coding
region of .alpha..sub.1A (1719 bp), including 150 bp of 5'
untranslated sequence (5' UT) and 300 bp of 3' untranslated
sequence (3' UT), was cloned into the BamHI and ClaI sites of the
polylinker-modified eukaryotic expression vector pCEXV-3, called
EXJ.HR (Bard et al, International Publication No. WO 94/08040,
published Apr. 14, 1994). The construct involved the ligation of
partial overlapping human lymphocyte genomic and hippocampal cDNA
clones: 5' sequences were contained on a 1.2 kb SmaI-XhoI genomic
fragment (the vector-derived BamHI site was used for subcloning
instead of the internal insert-derived SmaI site) and 3' sequences
were contained on 1.3 kb XhoI-ClaI cDNA fragment (the ClaI site was
from the vector polylinker). Stable cell lines were selected as
described above.
[0177] .alpha..sub.1B Human Adrenergic Receptor: The entire coding
region of .alpha..sub.1B (1563 bp), including 200 basepairs and 5'
untranslated sequence (3' UT) and 600 bp of 3' untranslated
sequence (3' UT), was cloned into the EcoRI site of pCEXV-3
eukaryotic expression vector (Bard et al, International Publication
No. WO 94/08040, published Apr. 14, 1994). The construct involved
ligating the full-length containing EcoRI brainstem cDNA fragment
from ZapII into the expression vector. The stable cell lines were
selected as described above.
[0178] .alpha..sub.1C Human Adrenergic Receptor: The entire coding
region of .alpha..sub.1C (1401 bp), including 400 basepairs of 5'
untranslated sequence (5' UT) and 200 p of 3' untranslated
sequences (3' UT), was cloned into the KpnI site of the
polylinker-modified pCEXV-3-derived eukaryotic expression vector,
EXJ.PH (Bard et al, International Publication No. WO 94/08040,
published Apr. 14, 1994). The construct involved ligation three
partial overlapping fragments: a 5' 0.6kb HindII genomic clone, a
central 1.8 EcoRI hippocampal cDNA clone, and a 3' 0.6 Kb PstI
genomic clone. The hippocampal cDNA fragment overlaps with the 5'
and 3' genomic clones so that the HincII and PstI sites at the 5'
and 3' ends of the cDNA clone, respectively, were utilized for
ligation. This full-length clone was cloned into the KpnI site of
the expression vector, using the 5' and 3' KpnI sites of the
fragment, derived from vector (i.e., pBluescript) and
3'-untranslated sequences, respectively. Stable cell lines were
selected as described above.
1TABLE 1 Binding and Functional Activities at Cloned Human
Alpha-Adrenergic Receptors Alpha-2 Alpha-1 Ex A B C A B C 1 pKi
7.74 7.13 7.15 5.17 4.61 5.28 pEC50 7.24 7.35 8.56 I.A 1.00 1.00
1.00 2 pKi 8.41 7.69 7.01 6.02 5.23 5.77 pEC50 9.53 7.73 8.93 I.A
1.00 1.00 1.00 3 pKi 8.12 7.81 7.00 6.27 5.09 5.72 pEC50 9.18 7.90
9.25 I.A 1.00 1.00 1.00 4 pKi 8.51 8.04 7.59 6.22 5.56 6.14 pEC50
9.41 8.01 9.45 I.A 1.00 1.00 1.00 5 pKi 8.45 7.51 7.62 6.27 5.74
5.65 pEC50 9.05 7.33 8.87 I.A 1.00 1.00 1.00 6 pKi 8.33 7.65 7.32
ND ND ND pEC50 8.17 7.65 8.40 I.A 1.00 1.00 1.00 7 pKi 8.45 7.55
7.38 6.57 5.91 5.75 pEC50 8.14 6.70 8.21 I.A 1.00 1.00 1.00 8 pKi
7.59 7.30 6.92 6.17 5.58 5.75 pEC50 6.87 6.63 7.68 I.A 0.90 0.80
1.00 9 pKi 7.74 7.33 6.81 5.56 4.87 5.17 pEC50 6.65 7.23 7.92 I.A
1.00 1.00 1.00 10 pKi 8.23 7.55 7.81 6.21 5.42 6.07 pEC50 8.52 6.99
8.63 I.A 1.00 1.00 1.00 11 pKi 7.09 6.65 5.95 5.00 4.45 5.24 pEC50
NA NA NA I.A 12 pKi 8.20 7.84 7.59 7.02 6.46 6.46 pEC50 7.27 7.51
7.76 I.A 1.00 1.00 1.00 13 pKi 7.85 6.44 6.40 4.98 4.03 5.53 pEC50
NA NA NA I.A 14 pKi 8.02 6.66 6.64 5.63 4.69 6.21 pEC50 6.60 NA NA
I.A 1.00 15 pKi 6.94 6.14 6.06 5.19 4.46 5.31 pEC50 NA NA NA I.A 16
pKi 8.25 7.91 7.38 7.26 6.29 6.38 pEC50 6.40 NA NA I.A 1.00 17 pKi
7.39 6.18 6.08 4.98 4.35 5.04 pEC50 NA NA NA I.A 1.00 18 pKi 8.35
6.43 6.55 5.57 4.70 6.05 pEC50 7.08 NA NA I.A 0.80 19 pKi 8.33 6.67
6.89 ND ND ND pEC50 6.31 NA NA I.A 0.70 20 pKi 6.62 6.14 6.20 4.83
4.23 4.95 pEC50 NA NA NA I.A 21 pKi 8.19 7.67 7.26 6.13 5.33 5.92
pEC50 6.60 NA NA I.A 0.90 22 pKi 8.10 6.37 6.74 4.98 3.98 5.73
pEC50 NA NA NA I.A 23 pKi 7.90 6.51 6.64 5.30 4.42 6.42 pEC50 6.16
NA NA I.A 0.90 24 pKi 8.48 7.89 7.47 6.51 5.31 6.60 pEC50 7.34 NA
NA I.A 1.00 25 pKi 7.79 6.19 6.36 5.21 4.35 5.01 pEC50 NA NA NA I.A
26 pKi 7.93 6.25 6.59 5.05 4.24 5.02 pEC50 NA NA NA I.A 27 pKi 7.03
5.99 6.14 5.08 4.47 5.16 pEC50 NA NA NA I.A 28 pKi 8.41 7.38 7.02
6.18 4.98 5.42 pEC50 NA NA NA I.A 29 pKi 7.58 6.44 6.31 6.04 4.68
5.85 pEC50 NA NA NA I.A 30 pKi 7.76 6.78 6.51 ND ND ND pEC50 NA NA
NA I.A 31 pKi 8.18 7.43 7.41 6.59 5.67 6.43 pEC50 NA NA NA I.A 32
pKi 7.96 7.30 6.79 5.43 4.48 5.41 pEC50 NA NA NA I.A 33 pKi 8.47
7.86 6.79 5.74 4.48 5.84 pEC50 NA NA NA I.A 34 pKi 7.42 7.05 6.73
5.59 4.92 5.87 pEC50 NA NA NA I.A 35 pKi 8.46 7.80 7.77 6.51 5.71
6.10 pEC50 NA NA NA I.A 36 pKi 8.02 6.97 6.78 6.09 4.96 5.19 pEC50
8.26 6.55 NA I.A 0.60 0.60 37 pKi 8.18 7.09 6.93 ND ND ND pEC50
7.69 NA 7.28 I.A 0.60 0.50 38 pKi 7.41 6.28 5.89 5.14 4.76 5.17
pEC50 7.45 6.80 6.44 I.A 1.00 0.80 1.00 39 pKi 7.36 6.31 6.21 5.80
4.96 5.32 pEC50 7.61 NA NA I.A 0.90 40 pKi 6.40 6.02 5.55 5.03 4.57
5.04 pEC50 6.14 NA NA I.A 0.80 42 pKi 7.99 7.63 6.67 5.79 5.07 5.09
pEC50 7.63 7.01 NA I.A 1.00 0.60 43 pKi 8.14 7.47 6.74 5.76 5.16
5.67 pEC50 7.64 6.79 7.09 I.A 1.00 0.80 0.90 44 pKi 8.53 7.33 6.67
5.69 5.23 5.51 pEC50 8.40 7.04 6.74 I.A 1.00 0.80 0.80 45 pKi 8.07
7.08 6.53 5.34 4.94 5.66 pEC50 7.28 6.07 7.92 I.A 1.00 0.70 0.60 46
pKi 7.34 6.98 5.83 5.15 4.55 4.97 pEC50 7.41 6.23 7.19 I.A 1.00
0.80 0.90 47 pKi 8.17 7.35 6.65 ND ND ND pEC50 7.33 6.94 7.34 I.A
1.00 0.80 0.80 48 pKi 7.11 6.18 6.61 5.91 7.31 6.92 pEC50 NA 6.70
8.87 I.A 0.80 0.60 49 pKi 7.71 7.44 6.67 ND ND ND pEC50 7.04 NA
7.65 I.A 0.80 1.00 50 pKi 8.16 8.63 7.61 7.45 6.78 6.11 pEC50 7.80
7.68 7.15 I.A 1.00 0.90 1.00 51 pKi 7.58 7.56 6.91 ND ND ND pEC50
7.01 7.05 8.37 I.A 0.90 0.60 1.00 52 pKi 7.61 7.11 6.90 ND ND ND
pEC50 7.09 7.14 8.26 I.A 0.90 0.80 1.00 53 pKi 7.83 7.74 7.05 6.51
5.72 6.00 pEC50 7.24 7.74 8.97 I.A 1.00 1.00 1.00 54 pKi 7.31 7.56
6.70 ND ND ND pEC50 5.90 6.88 7.69 I.A 0.70 0.60 0.90 55 pKi 7.36
6.68 6.37 ND ND ND pEC50 7.29 NA 6.79 I.A 0.60 0.80 56 pKi 7.66
6.74 6.69 5.90 5.29 6.23 pEC50 6.30 6.86 7.89 I.A 0.70 0.30 1.00 57
pKi 7.78 7.22 6.87 ND ND ND pEC50 NA 5.07 7.82 I.A 0.50 1.00 58 pKi
8.89 8.76 7.51 ND ND ND pEC50 8.61 7.55 8.49 I.A 1.00 0.50 1.00 59
pKi 9.01 8.10 7.78 ND ND ND pEC50 9.08 7.39 8.89 I.A 1.00 0.90 1.00
60 pKi 9.05 9.33 7.79 6.85 6.5 6.32 pEC50 9.23 7.75 9.4 I.A 1 0.9 1
C pKi 8.03 8.09 7.52 6.29 5.62 6.01 pEC50 8.09 6.79 7.26 I.A 1 1 1
NA: Not Active ND: Not Determined C: Clonidine
[0179] The protocols used to obtain these data are described in
Example 61.
EXAMPLE 62
[0180] Assay to measure analgesic activity of test compounds
[0181] Warm-Water Tail Withdrawal Assay (Butelman, E. R.; Woods, J.
H. J. Pharmacol. E. Therapeut. 1993, 264, 7620)
[0182] Subjects. Adult rhesus monkeys (Macaca mulatta) of either
sex were housed individually with free access to water. They were
fed fresh fruit weekly and approximately 40 biscuits (Purina Monkey
Chow) daily.
[0183] Apparatus and procedure. Tail withdrawal latencies were
timed manually using a microprocessor (IBM PCjr) via a push button
switch. Monkeys were seated in primate restraining chairs, and the
lower portion of the shaved tail (approximately 10 cm) was immersed
in a thermos flask containing water maintained at either 40, 50 or
55.degree. C. A maximum allowed latency of 20 seconds was recorded
if the monkeys failed to remove their tails by this time. Sessions
began with control determinations at each water temperature,
presented in a varied order between the subjects. In order for a
subject to be used, its withdrawal latency at 40.degree. C. had to
reach 20 seconds. After control determinations, drugs were
administered every 30 minutes using a cumulative dosing procedure
in which doses increased in 0.25 or 0.5 log units with each cycle.
Fifteen minutes after each injection, the subjects were tested at
the three temperatures in varying order, with tests being separated
from each other by approximately 2 minutes. In time course studies,
a single drug dose was administered after control determination,
with testing following at 30 minute intervals.
[0184] Design. Clonidine and compound 4 were studied up to doses
that produced near maximal withdrawal latencies in 55.degree. C.
water. The same three subjects were studied in all the above
experiments.
[0185] Sedation and Muscle Relaxation.
[0186] Procedure. Monkeys were trained to receive subcutaneous
injections while in their home cages; they were rated by one
non-blind observer familiar with the individual subjects, according
to modified rating scales for sedation and muscle relaxation (Table
2). Separate scales describe increasing degrees of sedation (as
measured by responsiveness to stimuli) and muscle relaxation (as
observed through changes in posture). Animals were injected in a
cumulative dosing procedure with a 30 minute interinjection
interval; observer rating on both scales took place approximately
15 minutes after each injection.
[0187] Design. Clonidine (0.032-1.0 mg/kg) and compound 4 (0.1-3.2
mg/kg) were studied using a cumulative dosing procedure. The same
three monkeys were typically studied under each se of
conditions.
[0188] Results: Using the procedures described above, compound 4
was found to be an effective analgesic agent with decreased
sedation relative to the reference compound, clonidine.
2TABLE 2 Modified sedation and muscle relaxation rating scales
Grade Sedation 0 No observable sedation 1 Monkey appears to stare
into space 2 Monkey is inattentive to ordinary movements of
observer 3 Monkey responds only to loud noises in the room 4 Monkey
responds only to opening of cage latch 5 Monkey responds only to
loud noises near its ear 6 Monkey responds only to touch
[0189]
3 Grade Muscle Relaxation 0 No observable muscle relaxation 1
Slight facial relaxation, jaw slackening, shoulder droop 2
Pronounced facial relaxation, jaw slackening, shoulder droop 3
Monkey must brace itself to sit up 4 Monkey cannot sit up
* * * * *