U.S. patent number RE32,400 [Application Number 06/760,608] was granted by the patent office on 1987-04-14 for substituted imidazole derivatives and their use as anti-thrombosis agents.
This patent grant is currently assigned to Farmos Yhtyma Oy. Invention is credited to Arto J. Karjalainen, Kauko O. A. Kurkela.
United States Patent |
RE32,400 |
Karjalainen , et
al. |
* April 14, 1987 |
Substituted imidazole derivatives and their use as anti-thrombosis
agents
Abstract
Compounds of the formula: ##STR1## wherein each of R.sub.1,
R.sub.2 and R.sub.3, which can be the same or different, is
hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy, amino,
hydroxy or nitro; R.sub.4 is hydrogen or alkyl or 1 to 7 carbon
atoms; R.sub.5 is hydrogen or a straight or branched alkyl group of
1 to 5 carbon atoms or a phenyl group; and R.sub.6 is hydrogen or
an alkyl group of 1 to 7 carbon atoms or a substituted or
unsubstituted benzyl, X is --CH.sub.2 --, --CHOH-- or --CH.dbd.CH--
and n is 0-4; provided that R.sub.5 and R.sub.6 are simultaneously
hydrogen only when n is 4 and X is --CH.dbd.CH--; and their
non-toxic pharmaceutically acceptable acid addition salts and
mixtures thereof exhibit valuable pharmacological activity and are
useful in the treatment of mammals, especially as antithrombotic
agents. Furthermore, some of the compounds have proved to possess
antihypertensive or .beta.-blocking activity. Antimicrobial and
antifungal properties have also been found. Processes for the
preparation of these compounds are described, as are novel
pharmaceutical compositions comprising at least one of the
compounds or their salts.
Inventors: |
Karjalainen; Arto J. (Oulu,
FI), Kurkela; Kauko O. A. (Oulu, FI) |
Assignee: |
Farmos Yhtyma Oy (Turku,
FI)
|
[*] Notice: |
The portion of the term of this patent
subsequent to April 17, 2001 has been disclaimed. |
Family
ID: |
10519480 |
Appl.
No.: |
06/760,608 |
Filed: |
July 30, 1985 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
345548 |
Feb 3, 1982 |
04514412 |
Apr 30, 1985 |
|
|
Foreign Application Priority Data
Current U.S.
Class: |
514/397; 548/235;
548/343.5; 548/346.1 |
Current CPC
Class: |
A61P
31/10 (20180101); C07D 233/56 (20130101); A61P
31/04 (20180101); A61P 31/00 (20180101); A61P
25/02 (20180101); A61P 9/12 (20180101); C07D
233/64 (20130101); A61P 7/02 (20180101) |
Current International
Class: |
C07D
233/54 (20060101); C07D 233/00 (20060101); A61K
031/415 (); C07D 233/54 (); C07D 233/66 (); C07D
263/30 () |
Field of
Search: |
;548/342,343,235
;514/397 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Lawson, J. Chem. Soc., 1957, pp. 4225-4228. .
Schubert, et al., CA 60:14495c. .
Wegner, et al., CA 85:46504a. .
Iwasaki, CA 86:106471z. .
J. Am. Chem. Soc., 95:1, 1973, pp. 284-285, Wuonola, et al. .
J. Org. Chem., 39, pp. 2301-2302, Noyce, et al. .
Chem. Abs., 71:124547u; Soniun, et al. .
Chem. Abs., 52:4494i, Lawson..
|
Primary Examiner: Jiles; Henry R.
Assistant Examiner: Whittenbaugh; Robert C.
Attorney, Agent or Firm: Armstrong, Nikaido, Marmelstein
& Kubovcik
Claims
We claim:
1. A substituted imidazole of the formula: ##STR30## wherein each
of R.sub.1, R.sub.2 and R.sub.3, which can be the same or
different, is hydrogen, chloro, bromo, fluoro, methyl, ethyl,
methoxy, amino, .[.hydroxy.]. or nitro and at least one of R.sub.1,
R.sub.2 and R.sub.3 is other than hydrogen; R.sub.4 is hydrogen or
an alkyl radical of 1 to 7 carbon atoms; R.sub.5 is hydrogen or a
straight or branched alkyl group of 1 to 5 carbon atoms or a phenyl
group; R.sub.6 is hydrogen or an alkyl group of 1 to 7 carbon atoms
or benzyl which is unsubstituted or substituted by chloro, bromo,
fluoro, methyl, ethyl, methoxy, amino, hydroxy or nitro; X is
--CH.sub.2 --, --CHOH-- or --CH.dbd.CH--; and n is 0-4, provided
that R.sub.5 and R.sub.6 are simultaneously hydrogen only when n is
4 and X is --CH.dbd.CH-- and that when n is 2, X is CHOH, R.sub. 1,
R.sub.2, R.sub.4 and R.sub.5 are all hydrogen, and R.sub.6 is
methyl, then R.sub.3 is a substituent other than 2-amino; and its
non-toxic, pharmaceutically acceptable acid addition salts.
2. A pharmaceutical composition useful for reducing or preventing
thrombosis comprising an effective amount of a compound selected
from the class consisting of a substituted imidazole of the
formula: ##STR31## wherein each of R.sub.1, R.sub.2 and R.sub.3,
which can be the same or different, is hydrogen, chloro, bromo,
fluoro, methyl, ethyl, methoxy, amino, hydroxy or nitro and at
least one of R.sub.1, R.sub.2 and R.sub.3 is other than hydrogen;
R.sub.4 is hydrogen or an alkyl radical of 1 to 7 carbon atoms;
R.sub.5 is hydrogen or a straight or branched alkyl group of 1 to 5
carbon atoms or a phenyl group; R.sub.6 is hydrogen or an alkyl
group of 1 to 7 carbon atoms or benzyl which is unsubstituted or
substituted by chloro, bromo, fluoro, methyl, ethyl, methoxy,
amino, hydroxy or nitro; X is --CH.sub.2 --, --CHOH-- or
--CH.dbd.CH--; n is 0-4, provided that R.sub.5 and R.sub.6 are
simultaneously hydrogen only when n is 4 and X is --CH.dbd.CH--;
and its non-toxic pharmaceutically acceptable acid addition salts,
and a compatible pharmaceutically acceptable carrier therefor.
3. A method of reducing and preventing thrombosis which comprises
administering to a patient subject thereto an effective amount of a
compound selected from the glass consisting of a substituted
imidazole of the formula: ##STR32## wherein each of R.sub.1,
R.sub.2 and R.sub.3, which can be the same or different, is
hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy, amino,
hydroxy or nitro and at least one of R.sub.1, R.sub.2 and R.sub.3
is other than hydrogen; R.sub.4 is hydrogen or an alkyl radical of
1 to 7 carbon atoms; R.sub.5 is hydrogen or a straight or branched
alkyl group of 1 to 5 carbon atoms or a phenyl group, R.sub.6 is
hydrogen or an alkyl group of 1 to 7 carbon atoms or benzyl which
is unsubstituted or substituted by chloro, bromo, fluoro, methyl,
ethyl, methoxy, amino, hydroxy, or nitro; X is --CH.sub.2 --,
--CHOH-- or CH.dbd.CH--; and n is 0-4, provided that R.sub.5 and
R.sub.6 are simultaneously hydrogen only when n is 4 and X is
--CH.dbd.CH--; and its non-toxic pharmaceutically acceptable acid
addition salts.
4. A method of reducing or preventing hypertension which comprises
administering to a patient subject thereto an effective amount of a
compound selected from the class consisting of a substituted
imidazole of the formula: ##STR33## wherein each of R.sub.1,
R.sub.2 and R.sub.3, which can be the same or different, is
hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy, amino,
hydroxy or nitro and at least one of R.sub.1, R.sub.2 and R.sub.3
is other than hydrogen; R.sub.4 is hydrogen or an alkyl radical of
1 to 7 carbon atoms; R.sub.5 is hydrogen or a straight or branched
alkyl group of 1 to 5 carbon atoms or a phenyl group; R.sub.6 is
hydrogen or an alkyl group of 1 to 7 carbon atoms or benzyl which
is unsubstituted or substituted by chloro, bromo, fluoro, methyl,
ethyl, methoxy, amino, hydroxy, or nitro; X is --CH.sub.2 -- and n
is 0 or 1; and its non-toxic pharmaceutically acceptable acid
addition salts.
5. A method of preventing the growth of, or killing, microbes which
comprises applying to a locus in which such microbes are, or may
be, present an effective amount of a compound selected from the
class consisting of a substituted imidazole of the formula:
##STR34## wherein each of R.sub.1, R.sub.2 and R.sub.3, which can
be the same or different, is hydrogen, chloro, bromo, fluoro,
methyl, ethyl, methoxy, amino, hydroxy or nitro and at least one of
R.sub.1, R.sub.2 and R.sub.3 is other than hydrogen; R.sub.4 is
hydrogen or an alkyl radical of 1 to 7 carbon atoms; R.sub.5 is
hydrogen or a straight or branched alkyl group of 1 to 5 carbon
atoms or a phenyl group; R.sub.6 is hydrogen or an alkyl group of 1
to 7 carbon atoms or benzyl which is unsubstituted or substituted
by chloro, bromo, fluoro, methyl, ethyl, methoxy, amino, hydroxy,
or nitro; X is --CH.dbd.CH--; and n is 1-4, provided that R.sub.5
and R.sub.6 are simultaneously hydrogen only when n is 4; and its
non-toxic pharmaceutically acceptable acid addition salts."
6. A compound according to claim 1 wherein each R.sub.1, R.sub.2
and R.sub.3, which can be the same or different, is hydrogen,
chloro, methyl, ethyl or methoxy, at least one being other than
hydrogen.
7. A compound according to claim 1 wherein R.sub.4 is hydrogen or
methyl.
8. A compound according to claim 1 wherein R.sub.4 is hydrogen.
9. 4-(2',6'-dimethylbenzyl)-2-methylimidazole and its non-toxic
pharmaceutically acceptable acid addition salts.
10. 4-(2',6'-dimethylbenzyl)-2-ethylimidazole and its non-toxic
pharmaceutically acceptable acid addition salts.
11. 4-(2',6'-dimethylbenzyl)-2-n-butylimidazole and its non-toxic
pharmaceutically acceptable acid addition salts.
12. 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-2-ethylimidazole
and its non-toxic pharmaceutically acceptable acid addition
salts.
13. 4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-3-benzylimidazole
and its non-toxic pharmaceutically acceptable acid addition
salts.
14. 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-benzylimidazole
and its non-toxic pharmaceutically acceptable acid addition
salts.
15. 4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-3-ethylimidazole
and its non-toxic pharmaceutically acceptable acid addition
salts.
16. 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-ethylimidazole
and its non-toxic pharmaceutically acceptable acid addition
salts.
17. 4-[5-(2',6'-dimethylphenyl)pentyl]-3-ethylimidazole and its
non-toxic pharmaceutically acceptable acid addition salts.
18. 4-[3-(2',6'-dimethylphenyl)propyl]-3-ethylimidazole and its
non-toxic pharmaceutically acceptable acid addition salts.
19. 4-[2-(2',6'-dimethylphenyl)ethyl]-2-methylimidazole and its
non-toxic pharmaceutically acceptable acid addition salts.
20. 4-(2',6'-dimethylbenzyl)-3-methylimidazole and its non-toxic
pharmaceutically acceptable acid addition salts.
21. 4-(2',6'-dimethylbenzyl)-3-ethylimidazole and its non-toxic
pharmaceutically acceptable acid addition salts.
22. 4-[3-(2',6'-dimethylphenyl)-1-propenyl]-2-ethylimidazole and
its non-toxic pharmaceutically acceptable acid addition salts.
23. 4-[4-(2',6'-dichlorophenyl)-1-butenyl]-2-methylimidazole and
its non-toxic pharmaceutically acceptable acid addition salts.
24. 4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-2-methylimidazole and
its non-toxic pharmaceutically acceptable acid addition salts.
25. 4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-5-methylimidazole and
its non-toxic pharmaceutically acceptable acid addition salts.
26. 4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-imidazole and its
non-toxic pharmaceutically acceptable acid addition salts.
27. 4-[6-(2'-chlorophenyl)-1-hexenyl]-imidazole and its non-toxic
pharmaceutically acceptable acid addition salts.
28. 4-[6-(2',6'-dichlorophenyl)-1-hexenyl]-5-methylimidazole and
its non-toxic pharmaceutically acceptable acid addition salts.
29. 4-[6-(2'-chlorophenyl)-1-hexenyl]-5-methylimidazole and its
non-toxic pharmaceutically acceptable acid addition salts.
Description
The present invention relates to substituted imidazole derivatives
and their non-toxic, pharmaceutically acceptable acid addition
salts, and their preparation, to pharmaceutical compositions
containing the same, and to their use.
The imidazole derivatives of the present invention have the general
formula: ##STR2## wherein each of R.sub.1, R.sub.2 and R.sub.3,
which can be the same or different, is hydrogen, chloro, bromo,
fluoro, methyl, ethyl, methoxy, amino, hydroxy or nitro; R.sub.4 is
hydrogen or an alkyl radical of 1 to 7 carbon atoms; R.sub.5 is
hydrogen or a straight or branched alkyl group of 1 to 5 carbon
atoms or a phenyl group; and R.sub.6 is hydrogen or an alkyl
radical of 1 to 7 carbon atoms or a substituted or unsubstituted
benzyl; X is --CH.sub.2, --CHOH-- or --CH.dbd.CH--; and n is an
integer from 0 to 4, provided that R.sub.5 and R.sub.6 are
simultaneously hydrogen only when n is 4 and X is --CH.dbd.CH--. It
will be appreciated that when R.sub.6 is hydrogen the two aforesaid
formulae are effectively the same. When R.sub.6 is substituted
benzyl it preferably carries up to 3 substituents selected from the
same radicals as R.sub. 1, R.sub.2 and R.sub.3.
The non-toxic pharmaceutically acceptable acid addition salts of
these compounds are also within the scope of the invention.
The compounds of formulae I are novel except for those in which n
is 0, X is CH.sub.2, R.sub.1, R.sub.2, R.sub.3 and R.sub.6 are all
hydrogen, R.sub.4 is hydrogen or ethyl, and R.sub.5 is methyl or
phenyl; n is 0, X is CHOH, R.sub.1, R.sub.2, R.sub.3 and R.sub.4
are all hydrogen and one or both of R.sub.5 and R.sub.6 is methyl;
and n is 2, X is CHOH, R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are
all hydrogen, R.sub.6 is methyl, and R.sub.3 is 2-amino. No
therapeutic utility has however been disclosed for the known
compounds.
The compounds of the formula (I) form acid addition salts with both
organic and inorganic acids. They can thus form many
pharmaceutically useable acid addition salts, as, for instance,
chlorides, bromides, sulfates, nitrates, phosphates, sulfonates,
formates, tartrates, maleates, citrates, benzoates, salicylates,
ascorbates and the like.
The invention includes within its scope pharmaceutical compositions
comprising at least one of the compounds of formula (I) or a
non-toxic, pharmaceutically acceptable salt thereof, and a
compatible pharmaceutically acceptable carrier therefor.
The present invention provides, for example, the following specific
compounds of formula (I) wherein X is --CH.sub.2 --:
4-(2'-methylbenzyl)-2-methylimidazole
4-(4'-methylbenzyl)-2-methylimidazole
4-(3'-methylbenzyl)-2-methylimidazole
4-(2'-chlorobenzyl)-2-methylimidazole
4-(2',6'-dimethylbenzyl)-2-methylimidazole
4-(2',3'-dimethylbenzyl)-2-methylimidazole
4-(2',5'-dimethylbenzyl)-2-methylimidazole
4-(2',6'-dichlorobenzyl)-2-methylimidazole
4-(2',6'-dimethylbenzyl)-2-ethylimidazole
4-(2'-chlorobenzyl)-2-ethylimidazole
4-(2',6'-dimethylbenzyl)-2-propylimidazole
4-(2',6'-dimethylbenzyl)-2-n-butylimidazole
4-(2',6'-dimethylbenzyl)-2-tert.butylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-2-methylimidazole
4-[2-(2',3'-dimethylphenyl)ethyl]-2-methylimidazole
4-[3-(2'-chlorophenyl)propyl]-2-methylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-2-methylimidazole
4-[4-(2'-chlorophenyl)butyl]-2-methylimidazole
4-[4-(2',6'-dimethylphenyl)butyl]-2-methylimidazole
4-[5-(2'-chlorophenyl)pentyl]-2-methylimidazole
4-[5-(2',6'-dimethylphenyl)pentyl]-2-methylimidazole
4-[2-(2'-chlorophenyl)ethyl]-2-ethylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-2-ethylimidazole
4-[2-(3'-chlorophenyl)ethyl]-2-propylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-2-tert.butylimidazole
4-[4-(2',6'-dimethylphenyl)butyl]-2-phenylimidazole
4-(2'-methylbenzyl)-1-methylimidazole
4-(4'-methylbenzyl)-1-methylimidazole
4-(3'-methylbenzyl)-1-methylimidazole
4-(2'-chlorobenzyl)-1-methylimidazole
4-(2',6'-dimethylbenzyl)-1-methylimidazole
4-(2',3'-dimethylbenzyl)-1-methylimidazole
4-(2',5'-dimethylbenzyl)-1-methylimidazole
4-(2',6'-dichlorobenzyl)-1-methylimidazole
4-(2',6'-dimethylbenzyl)-1-ethylimidazole
4-(2'-chlorobenzyl)-1-ethylimidazole
4-(2',6'-dimethylbenzyl)-1-propylimidazole
4-(2',6'-dimethylbenzyl)-1-n-butylimidazole
4-(2',6'-dimethylbenzyl)-1-tert.butylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-1-methylimidazole
4-[2-(2',3'-dimethylphenyl)ethyl]-1-methylimidazole
4-[3-(2'-chlorophenyl)propyl]-1-methylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-1-methylimidazole
4-[4-(2'-chlorophenyl)butyl]-1-methylimidazole
4-[4-(2',6'-dimethylphenyl)butyl]-1-methylimidazole
4-[5-(2'-chlorophenyl)pentyl]-1-methylimidazole
4-[5-(2',6'-dimethylphenyl)pentyl]-1-methylimidazole
4-[2-(2'-chlorophenyl)ethyl]1-ethylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-1-ethylimidazole
4-[2-(3'-chlorophenyl)ethyl]-1-propylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-1-tert.butylimidazole
4-(2',6'-dimethylbenzyl)-1-benzylimidazole
4,1-bis(2'-methylbenzyl)imidazole
4,1-bis(2',3'-dimethylbenzyl)imidazole
4,1-bis(3',4'-dimethylbenzyl)imidazole
4,1-bis(2',6'-dimethylbenzyl)imidazole
4,1-bis(2'-chlorobenzyl)imidazole
4-(2',6'-dimethylbenzyl)-3-benzylimidazole
4,3-bis(2'-methylbenzyl)imidazole
4,3-bis(2',3'-dimethylbenzyl)imidazole
4,3-bis(3',4'-dimethylbenzyl)imidazole
4,3-bis(2',6'-dimethylbenzyl)imidazole
4,3-bis(2'-chlorobenzyl)imidazole
4-(2'-methylbenzyl)-3-methylimidazole
4-(4'-methylbenzyl)-3-methylimidazole
4-(3'-methylbenzyl)-3-methylimidazole
4-(2'-chlorobenzyl)-3-methylimidazole
4-(2',6'-dimethylbenzyl)-3-methylimidazole
4-(2',3'-dimethylbenzyl)-3-methylimidazole
4-(2',5'-dimethylbenzyl)-3-methylimidazole
4-(2',6'-dichlorobenzyl)-3-methylimidazole
4-(2',6'-dimethylbenzyl)-3-ethylimidazole
4-(2'-chlorobenzyl)-3-ethylimidazole
4-(2',6'-dimethylbenzyl)-3-propylimidazole
4-(2',6'-dimethylbenzyl)-3-n-butylimidazole
4-(2',6'-dimethylbenzyl)-3-tert.butylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-3-methylimidazole
4-[2-(2',3'-dimethylphenyl)ethyl]-3-methylimidazole
4-[3-(2'-chlorophenyl)propyl]-3-methylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-3-methylimidazole
4-[4-(2'-chlorophenyl)butyl]-3-methylimidazole
4-[4-(2',6'-dimethylphenyl)butyl]-3-methylimidazole
4-[5-(2'-chlorophenyl)pentyl]-3-methylimidazole
4-[5-(2',6'-dimethylphenyl)pentyl]-3-methylimidazole
4-[2-(2'-chlorophenyl)ethyl]-3-ethylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-3-ethylimidazole
4-[2-(3'-chlorophenyl)ethyl]-3-propylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-3-tert.butylimidazole
4-(2',6'-dimethylbenzyl)-5-methyl-1-methylimidazole
4-(2',3'-dimethylbenzyl)-5-methyl-1-methylimidazole
4-(2'-methylbenzyl)-5-methyl-1-methylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-2-methyl-1-methylimidazole
4-[2-(2',3'-dimethylphenyl)ethyl]-2-methyl-1-methylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-2-methyl-3-methylimidazole
4-(2',6'-dimethylbenzyl)-1-(2'-chlorobenzyl)-imidazole
4-(2',6'-dimethylbenzyl)-3-(2'-chlorobenzyl)-imidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-1-(4'-methylbenzyl)-imidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-3-(4'-methylbenzyl)-imidazole
4-(2',3'-dimethylbenzyl)-1-(4'-methylbenzyl)-imidazole
4-(2',3'-dimethylbenzyl)-3-(4'-methylbenzyl)-imidazole
4-(2',6'-dimethylbenzyl)-1-(3'-methylbenzyl)-imidazole
4-(2',6'-dimethylbenzyl)-3-(3'-methylbenzyl)-imidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-1-(2'-methylbenzyl)-imidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-1-(2',6'-dichlorobenzyl-imidazole
4-(2',3'-dimethylbenzyl)-1-(2',6'-dichlorobenzyl)-imidazole
4-(2',3'-dimethylbenzyl)-3-(2',6'-dichlorobenzyl)-imidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-1-benzylimidazole
4-[5-(2',6'-dimethylphenyl)pentyl]-3-ethylimidazole
4-[2-(2',6'-dimethylphenyl)ethyl]-3-ethylimidazole
The following specific compounds of formula (I) wherein X is
--CHOH--;
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-ethylimidazole
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-n-butylimidazole
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-2-methylimidazole
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-phenylimidazole
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-methylimidazole
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-2-methylimidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-2-ethylimidazole
4-[4-(2'-chlorophenyl)-1-hydroxybutyl]-2-methylimidazole
4-[4-(2',6'-dichlorophenyl)-1-hydroxybutyl]-2-methylimidazole
4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-2-methylimidazole
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-(2'-chlorobenzyl)imidazol
e
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-3-(3'-methylbenzyl)imidazol
e
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-benzylimidazole
4-[.alpha.-(3'-methylphenyl)hydroxymethyl]-3-benzylimidazole
4-(2-phenyl-1-hydroxyethyl)-3-benzylimidazole
4-[.alpha.-(4'-chlorophenyl)hydroxymethyl]-3-benzylidazole
4-(3-phenyl-1-hydroxypropyl)-3-benzylimidazole
4-[3-(3',4'-dimethylphenyl)-1-hydroxypropyl]-3-benzylimidazole
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-(4'-chlorobenzyl)imidazol
e
4-[.alpha.-(3'-methylphenyl)hydroxymethyl]-3-(4'-chlorobenzyl)imidazole
4-(2-phenyl-1-hydroxyethyl]-3-(4'-chlorobenzyl)imidazole
4-[.alpha.-(4'-chlorophenyl)hydroxymethyl]-3-(4'-chlorobenzyl)imidazole
4-(3-phenyl-1-hydroxypropyl)-3-(4'-chlorobenzyl)imidazole
4-[3-(3',4'-dimethylphenyl)-1-hydroxypropyl]-3-(4'-chlorobenzyl)-imidazole
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-(4'-methylbenzyl)imidazol
e
4-[.alpha.-(3'-methylphenyl)hydroxymethyl]-3-(4'-methylbenzyl)imidazole
4-(2-phenyl-1-hydroxyethyl)-3-(4'-methylbenzyl)imidazole
4-[.alpha.-(4'-chlorophenyl)hydroxymethyl]-3-(4'-methylbenzyl)imidazole
4-(3-phenyl-1-hydroxypropyl)-3-(4'-methylbenzyl)imidazole
4-[3-(3',4'-dimethylphenyl)-1-hydroxypropyl]-3-(4'-methylbenzyl)imidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-benzylimidazole
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-3-benzylimidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-ethylimidazole
4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-3-ethylimidazole
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-3-ethylimidazole
and the following specific compounds of formula (I) wherein X is
--CH.dbd.CH--;
4-[2-(2',6'-dimethylphenyl)ethenyl]-2-methylimidazole
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-2-ethylimidazole
4-[4-(2'-chlorophenyl)-1-butenyl]-2-methylimidazole
4-[4-(2'-chlorophenyl)-1-butenyl]-2-ethylimidazole
4-[4-(2',6'-dichlorophenyl)-1-butenyl]-2-methylimidazole
4-[4-(2',4'-dichlorophenyl)-1-butenyl]-2-methylimidazole
4-[4-(2'-methylphenyl)-1-butenyl]-2-ethylimidazole
4-[4-(3'-methylphenyl)-1-butenyl]-2-ethylimidazole
4-[4-(2',6'-dimethylphenyl)-1-butenyl]-2-methylimidazole
4-[4-(2',3'-dimethylphenyl)-1-butenyl]-2-methylimidazole
4-[5-(2'-chlorophenyl)-1-pentenyl]-2-methylimidazole
4-[5-(2',6'-dichlorophenyl)-1-pentenyl]-2-ethylimidazole
4-[5-(2',4'-dichlorophenyl)-1-pentenyl]-2-ethylimidazole
4-[5-(2'-methylphenyl)-1-pentenyl]-2-methylimidazole
4-[5-(3'-methylphenyl)-1-pentenyl]-2-methylimidazole
4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-2-methylimidazole
4-[5-(2',3'-dimethylphenyl)-1-pentenyl]-2-methylimidazole
4-[6-(2'-chlorophenyl)-1-hexenyl]-2-ethylimidazole
4-[6-(2',6'-dichlorophenyl)-1-hexenyl]-2-ethylimidazole
4-[6-(2',4'-dichlorophenyl)-1-hexenyl]-2-ethylimidazole
4-[6-(2'-methylphenyl)-1-hexenyl]-2-methylimidazole
4-[6-(3'-methylphenyl)-1-hexenyl]-2-methylimidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-2-methylimidazole
4-[6-(2',3'-dimethylphenyl)-1-hexenyl]-2-methylimidazole
4-[4-(2'-chlorophenyl)-1-butenyl]-1-methylimidazole
4-[4-(2',6'-dimethylphenyl)-1-butenyl]-1-methylimidazole
4-[5-(2'-methylphenyl)-1-pentenyl]-1-methylimidazole
4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-1-ethylimidazole
4-[6-(2'-methylphenyl)-1-hexenyl]-1-ethylimidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-1-ethylimidazole
4-[4-(2'-chlorophenyl)-1-butenyl]-3-methylimidazole
4-[4-(2',6'-dimethylphenyl)-1-butenyl]-3-methylimidazole
4-[5-(2'-methylphenyl)-1-pentenyl]-3-methylimidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-imidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-5-methylimidazole
4-[6-(2',6'-dichlorophenyl)-1-hexenyl]-5-methylimidazole
4-[6-(2'-chlorophenyl)-1-hexenyl]-imidazole
4-[6-(2'-chlorophenyl)-1-hexenyl]-5-methylimidazole
4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-3-ethylimidazole
4-[6-(2'-methylphenyl)-1-hexenyl]-3-ethylimidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-3-ethylimidazole
4-[2-(2',6'-dimethylphenyl)ethenyl]-3-benzylimidazole
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-3-benzylimidazole
4-[2-(2',6'-dimethylphenyl)ethenyl]-3-ethylimidazole
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-3-ethylimidazole
The compounds of the present invention have been found to possess
excellent antithrombotic activity. Preliminary tests have shown
that they also possess other valuable pharmacological properties,
for example, antihypertensive and .beta.-blocking effects.
Antimicrobial and antifungal properties have also been found.
While all of the compounds of formula (I) have the aforementioned
activities, certain groups of compounds remain preferred. One such
preferred group can be represented by the structural formula:
##STR3## wherein n and R.sub.5 and R.sub.6 are the same as before;
each of R'.sub.1, R'.sub.2 and R'.sub.3, is hydrogen, chloro,
methyl, ethyl, methoxy or hydroxy; and R'.sub.4 is hydrogen, methyl
or ethyl. Preferably at least one of R'.sub.1, R'.sub.2 and
R'.sub.3 is other than hydrogen.
According to a feature of the invention, the compounds of formula
(I) in which X is --CHOH-- are made by a Grignard reaction in which
an imidazole aldehyde of the formula: ##STR4## wherein R.sub.4,
R.sub.5 and R.sub.6 are as defined before, is reacted with an
arylalkyl magnesium halide derivative of the formula: ##STR5##
wherein R.sub.1, R.sub.2, R.sub.3 and n are as defined before and
Hal is a halogen atom.
The arylalkylmagnesium halide derivative can be, for example, an
arylalkylmagnesiumbromide derivative, which is prepared by reacting
the corresponding arylalkylbromide derivative with magnesium.
Suitable solvents for the reaction include a variety of ethers,
preferably tetrahydrofura. The arylalkylmagnesiumhalide derivative
is prepared in the usual way by adding the arylalkylmagnesiumhalide
derivative in a suitable solvent, e.g. tetrahydrofuran, dropwise
onto magnesium turnings covered by tetrahydrofuran, at the boiling
point of the reaction mixture. When the magnesium turnings have
reacted, the mixture is cooled slightly and the 4-imidazole
derivative is added in solid form in small portions. After the
addition, the reaction mixture is refluxed until all of the
4-imidazole derivative has reacted. The reaction time varies
between one and five hours.
It is surprising that in the above described Grignard reaction a
compound of the formula (III) ##STR6## wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are the same as before, is
formed. The amount of the compounds of the formula (III), which can
be isolated from the reaction mixture depends on the structure of
the derivatives, the reaction time, and the amount of Grignard
reagent used. Thus when one and a half equivalents of a longer
chained Grignard reagent are reacted with the aldehyde derivative
using relatively shorter reaction times than usually, from about
one half to two hours, the amount of the compound of formula (III)
can be as high as 50% of the isolated products.
Another process for the preparation of compounds of the present
invention, in which X is --CHOH-- comprises reducing a compound of
the formula (III) to a compound of formula (I) wherein X is
--CHOH--. The reduction is performed by usual methods, for example
using sodium borohydride in ethanol.
A two-stage process for the preparation of compounds of the present
invention wherein X is --CH.sub.2 -- comprises a first stage
wherein a compound of the formula (I) in which X is --CHOH-- is
dehydrated to a compound of the formula (IV) ##STR7## wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are
defined as before, and a second stage, wherein the compound of the
formula (IV) is hydrogenated to a compound of the formula (I) in
which X is --CH.sub.2 --.
The dehydration is preferably performed by refluxing in an
appropriate acidic solution, e.g. concentrated hydrochloric acid or
heating for example with potassium hydrogen sulfate. In the second
stage the hydrogenation is conveniently carried out at room
temperature with good stirring in the above mentioned acidic
solution in the presence of a catalyst in a hydrogen atmosphere.
Suitable catalysts are for example platinum oxide,
palladium-on-carbon or Raney-nickel.
A further process for the preparation of the compounds of the
formula (I) in which X is --CH.sub.2 -- comprises hydrolysing a
corresponding compound of the formula: ##STR8## wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are as defined
before. Preferably, the hydrolysis is carried out by boiling the
starting material, an N-acylated imidazole derivative, in an
aqueous solution of an inorganic acid until the reaction is
completed.
Yet another process for the preparation of the compounds of formula
(I) in which X is --CH.sub.2 -- or CHOH, comprises hydrogenating a
starting material of the formula: ##STR9## wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are as defined
before and R.sub.7 is an alkyl or an aryl group. The hydrogenation
is conveniently conducted in the presence of a suitable catalyst
and under a hydrogen atmosphere, with stirring. Suitable catalysts
include platinum oxide, palladium-on-carbon and Raney nickel.
Reaction temperatures vary with the particular starting material
employed, with typical temperatures being 25.degree.-70.degree.
C.
Yet another process for the preparation of the compounds of formula
(I), wherein X is --CH.sub.2 -- or CHOH, comprises hydrogenation of
the benzyl group R.sub.8 CH.sub.2 -- of a starting material of the
formula: ##STR10## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and n are as defined before and R.sub.8 is a substituted or
an unsubstituted phenyl group. The hydrogenation is conveniently
conducted in liquid ammonia with sodium at a lowered
temperature.
The present invention further provides yet another process for
preparing compounds of the invention in which X is --CH.sub.2 --.
Thus, according to this embodiment of the invention, a starting
material of the formula V: ##STR11## wherein R.sub.1, R.sub.2,
R.sub.3 and n are as hereinbefore defined; wherein R.sub.9,
R.sub.10, R.sub.11 and R.sub.12, which can be the same or
different, are each hydrogen, or alkyl of 1 to 7 carbon atoms,
hydroxy, halogen, amino, --O-- alkyl of 1 to 7 carbon atoms or
##STR12## wherein R.sub.6 is defined as before; or wherein R.sub.12
and R.sub.10 can be combined to form a keto group, or R.sub.9 and
R.sub.11 can be combined to form a keto group, or both R.sub.12 and
R.sub.10 and R.sub.9 and R.sub.11 can simultaneously form keto
groups; is reacted with a reagent capable of converting said
starting material to the corresponding imidazole of the formula:
##STR13## wherein R.sub.1, R.sub.2, R.sub.3 and n are defined as
before. Reagents capable of converting the depicted starting
material to the corresponding imidazole include ##STR14## wherein
R.sub.5 and R.sub.6 are as before.
A surprising aspect of the above mentioned reaction is the fact
that the hydroxyacetal starting materials, e.g., compounds of the
formula: ##STR15## react with ##STR16## to form the corresponding
imidazoles.
Yet another method for the preparation of the compounds of formula
(I) wherein X is --CH.sub.2 -- comprises reacting a
N-trialkylsilylimidazole of the formula ##STR17## wherein Y is an
alkyl group, preferably methyl, with an arylalkylhalogenide of the
formula ##STR18## wherein R.sub.1, R.sub.2, R.sub.3 and n are as
before and Hal is a halogen atom, in the presence of a Lewis acid,
for example titanium tetrachloride, aluminium chloride or zinc
chloride. As solvent can be used for example methylene chloride or
chloroform. The reaction is preferably carried out at room
temperature stirring the starting materials for 6-12 hours.
According to a feature of the invention, the compounds of formula
(I) wherein X is --CH.dbd.CH--, are prepared, by dehydration of the
corresponding imidazoles of the formula: ##STR19## wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are defined as
before and n is 1-5. The dehydration is carried out according to
known methods for instance by refluxing the hydroxysubstituted
compound in an appropriate acidic solution, e.g. concentrated
hydrochloric acid. Alternatively the hydroxysubstituted imidazole
can be dehydrated by heating it together with anhydrous potassium
hydrogen sulfate.
Another process for the preparation of compounds of formula (I),
wherein X is --CH.dbd.CH--, is a Wittig reaction which comprises
reacting an imidazole aldehyde of the formula: ##STR20## wherein
R.sub.4, R.sub.5 and R.sub.6 are the same as before, with an
aralkylidenetriphenylphosphorane of the formula: ##STR21## wherein
R.sub.1, R.sub.2 and R.sub.3 are the same as before and n is 0-4.
The aralkylidenetriphenylphosphoranes are preferably prepared by
reacting the corresponding aralkyltriphenylphosphonium halide of
the formula: ##STR22## wherein R.sub.1, R.sub.2 and R.sub.3 are the
same as before, n is 0-5 and Hal is a halogen atom, with a basic
reagent, preferably butyllithium.
The processes described above for the preparation of compounds of
formula (I), wherein X is --CH.dbd.CH--, result mainly in the trans
isomer of the compound. The trans isomer can be converted to the
cis isomer according to known methods, e.g. by heating it in the
presence of an acid or by irradiating it with ultraviolet
light.
A method for the preparation of compounds of formula (I) wherein
R.sub.6 is an alkyl of 1 to 7 carbon atoms or benzyl, comprises
alkylation of a compound of the formula ##STR23## wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, X and n are as defined before
with a compound of the formula ##STR24## wherein R.sub.6 is an
alkyl group of 1 to 7 carbon atoms or a substituted or
unsubstituted benzyl, Hal is a halogen atom and R is a sulphuric
acid residue, for example p-tolyl.
The alkylation can be performed for example by reacting an
alkylhalide or an alkyltosylate in dimethylformamide in the
presence of sodium hydride with the starting imidazole. From the
mixture obtained containing 1--R.sub.6 -- and 3--R.sub.6
--imidazole derivative, the components can be separated for example
by crystallization or column chromatographically.
The alkylation can also be performed as a phase-transfer reaction
through the reaction of the starting imidazole derivatives with the
alkylhalide or the alkyltosylate in the presence of a phase
transfer reagent, for example triphenylbenzylammoniumchloride or
tetrabutylammoniumhydrogensulfate in an alkaline water
solution.
Another method for the preparation of compounds of formula (I)
wherein R.sub.6 is an alkyl group of 1-7 carbon atoms or a
substituted or unsubstituted benzyl, R.sub.5 is hydrogen and X is
--CH.sub.2 --, is a so-called TosMIC reaction.
(TosMIC=p-toluenesulfonylmethylisocyanide). This method gives
specific isomers of the formula ##STR25## wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.6 and n are as before.
This method comprises reacting a p-toluenesulfonylmethylisocyanide
compound of the formula ##STR26## wherein R.sub.4 is as defined
before, with a primary amine of the formula R.sub.6 NH.sub.2 and an
aldehyde of the formula ##STR27## or with an imine of the formula
##STR28## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.6 and n are as
before, to give the corresponding imidazole of the formula
##STR29##
The reaction is carried out in an alkaline solution of methanol or
dimethoxyethane. The reaction is performed either with an excess of
primary amine or in the presence of sodium carbonate or potassium
carbonate. The temperature ranges from room temperature to the
boiling point of the solvent.
As stated herein above, the compounds of the general formula (I)
and their non-toxic, pharmaceutically acceptable acid addition
salts have valuable pharmacological properties and have been found
to possess excellent antithrombotic properties.
Tests have shown that they also possess other pharmacological
properties as well, for example, antihypertensive and
.beta.-blocking activity. Furthermore, antimicrobial and antifungal
properties have been found, too.
Administration of isomeric compounds of formula (I), their
non-toxic, pharmaceutically acceptable acid salts or mixtures
thereof may be achieved parenterally, intravenously or orally.
Typically, an effective amount of the derivative is combined with a
suitable pharmaceutical carrier. As used herein, the term
"effective amount" encompasses those amounts which yield the
desired activity without causing adverse side-effects. The precise
amount employed in a particular situation is dependent upon
numerous factors such as method of administration, type of mammal,
condition for which the derivative is administered, etc., and of
course the structure of the derivative.
The pharmaceutical carriers which are typically employed with the
derivatives of the present invention may be solid or liquid and are
generally selected with the planned manner of administration in
mind. Thus, for example, solid carriers include lactose, sucrose,
gelatin and agar, while liquid carriers include water, syrup,
peanut oil and olive oil. Other suitable carriers are well-known to
those skilled in the art of pharmaceutical formulations. The
combination of the derivative and the carrier may be fashioned into
numerous acceptable forms, such as tablets, capsules,
suppositories, solutions, emulsions, and powders.
The clinical dosage ranges for the compounds of the invention have
been estimated for oral administration antithrombotic and
antihypertensive agents, 0.2 to 2 mg/kg per day and antimicrobial
agents 0.3 to 3 mg/kg per day.
Acute toxicity (LD.sub.50) ranges from 15 to 100 mg/kg i.v. in mice
for the tested compounds.
The anti-hypertensive properties of the imidazole derivatives of
the present invention have been determined by the following
procedure. Sprague-Dawley rats of normal weight were first
anesthetized with urethane. After this, the femoral artery was
connected by way of a polyethylene tube with a blood pressure
transducer. The test substance was then injected into the femoral
vein and the blood pressure and the pulse frequency were registered
with a recorder.
The antithrombotic activity was investigated in vitro. The
inhibiting activity of the compounds against ADP- and
collagen-induced aggregation of thrombocytes was measured. In the
test thrombocytes from a cow were used. To 1.2 ml of plasma
containing 250000 thrombocytes/mm.sup.3 were added 50 .mu.l of a
solution of the compound to be tested. After 10 min incubation
either ADP or collagen was added. The aggregation of the
thrombocytes was turbidimetrically determined at .gamma.=605 n
m.
The antimicrobial activity was determined in vitro according to a
qualitative test for antibacterial and antifungal activity, using
the agar diffusion method, against the following standard
organisms: Staphylococcus aureus, Streptococcus pyogenes,
Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa,
Candida albicans and Aspergillus niger.
The antimycotic activity was determined in vitro against the
following dermatophytes and fungi species: Trichophyton rubrum,
Trichophyton mentagrophytes, Microsporum canis, Epidermophyton
floccosum, Chrysosporum, Candida albicans, Candida guilliermondi,
Candida parapsilosis, Torulopsis glabrata and Saccharomyces
cerevisiae. The fungi were cultured by plating on an agar nutrient
medium. The compound to be tested was added before the incubation.
A measure of the efficiency of te compound tested is the radius of
the circle, within which the growth of the fungi has been
inhibited.
The .beta.-blocking activity was measured in vitro as follows: The
attrium of a guinea-pig was isolated. The inhibiting activity of
the compound against isoprenaline-induced chronotropic and
inotropic action in the isolated atrium was measured.
Acute toxicity was determined by using female mice of NMRI-Strain
with an age of about 7 months and weighing 30-40 g. The
administration of the test compound was i.v.
In the antithrombotic activity test, the compound
4-(2',6'-dimethylbenzyl)-2-methylimidazole, which has a LD.sub.50
of 15 mg/kg i.v. in mice, inhibited the collagen-induced and the
ADP-induced aggregation of thrombocytes clearly.
In the same test, all the following compounds inhibited the
collagen-induced and the ADP-induced aggregation of thrombocytes
effectively:
4-(2',6'-dimethylbenzyl)-2-ethylimidazole
4-(2',6'-dimethylbenzyl)-2-n-butylimidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-2-ethylimidazole
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-3-benzylimidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-benzylimidazole
4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-3-ethylimidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-ethylimidazole
4-[5-(2',6'-dimethylphenyl)pentyl-3-ethylimidazole
4-[3-(2',6'-dimethylphenyl)propyl]-3-ethylimidazole
In the antihypertensivity test, the compound
4-(2',6'-dimethylbenzyl)-2-methylimidazole caused at a dose of
0.1-3 mg/kg about 25 percent lowering of the blood pressure
measured 20 minutes after administration. At the same dose the
pulse frequency decreased with about 30 percent.
For example the following compounds proved to possess
antihypertensive activity, too:
4-[2-(2',6'-dimethylphenyl)ethyl]-2-methylimidazole
4-(2',6'-dimethylbenzyl)-3-methylimidazole
4-(2',6'-dimethylbenzyl)-3-ethylimidazole
In the antimicrobial tests for example the following compounds were
active against all the species:
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-2-ethylimidazole
4-[4-(2',6'-dichlorophenyl)-1-butenyl]-2-methylimidazole
4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-2-methylimidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-5-methylimidazole
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-imidazole
4-[6-(2'-chlorophenyl)-1-hexenyl]-imidazole
4-[6-(2',6'-dichlorophenyl)-1-hexenyl]-5-methylimidazole
4-[6-(2'-chlorophenyl)-1-hexenyl]-5-methylimidazole
In the Examples below, where I.sub.H -NMR spectrum shifts are
presented, the NMR spectra were determined with a Perkin-Elmer R 24
apparatus using an external tetramethylsilane standard, from which
the presented chemical shifts (.delta.,ppm) are tabulated. The
letters s, d, t and m are used to indicate a singlet, doublet,
triplet or multiplet, respectively. In the same connection, the
number of hydrogen atoms is also stated. The compounds which are
indicated as bases are tested in deuterium methanol, deuterium
acetone or deuterium chloroform, while the values for compounds
which are indicated as hydrochlorides were determined in deuterium
oxide. The presented .sup.13 C-NMR-spectrum were determined with a
Bruker WB-80 DS apparatus.
The following Examples illustrate the invention.
EXAMPLE 1
4-[.alpha.-(2',6'-dimethylphenyl)-hydroxymethyl]-2-ethylimidazole
6.12 g of dry magnesium turnings are covered with 100 ml of dry
tetrahydrofuran (THF). The mixture is heated to boiling and a
solution of 46.7 g of 1-bromo-2,6-dimethylbenzene in 100 ml of dry
tetrahydrofuran is added dropwise at such a rate that gentle
refluxing is maintained. After the addition is complete, the
reaction mixture is refluxed for an additional 30 minutes. The
reaction mixture is cooled to 50.degree. C. and 10.45 g of
2-ethyl-4-imidazolealdehyde is added slowly in small portions.
After the addition is complete, the mixture is refluxed for 4
hours. Then the reaction mixture is cooled and poured into 200 ml
of cold water containing 20 ml of concentrated hydrochloric acid.
Part of the tetrahydrofuran is distilled off to give a smaller
volume and the tetrahydrofuran is replaced with water. The mixture
is washed twice with 50 ml portions of chloroform. The aqueous
layer is made alkaline with sodium hydroxide solution (pH about 8).
The precipitate which forms is washed with water and added to 100
ml of 4N NaOH solution and the mixture is stirred vigorously for
one hour. The precipitate is filtered, washed several times with
water and dried. The crude product is recrystallized from a mixture
of water and ethanol to give 7.8 g of a product melting at
164.degree.-166.degree. C.
.sup.1 H-NMR: 1.25 (t, 3H), 2.33 (s, 6H), 2.681 (q, 2H), 4.86 (s,
1H+H.sub.2 O), 6.22 (s, 1H), 6.36 (s, 1H), 7.00 (s, 3H)
.sup.13 C-NMR:13.25 (q, 1C), 20.91 (q, 2C), 22.36 (t, 1C), 67.49
(d, 1C), 118.17 (d, 1C), 128.25 (s, 2C), 129.95 (d, 2C), 138.06 (d,
1C), 139.03 (s, 1C), 139.33 (s, 1C), 151.321 (s, 1C).
EXAMPLE 2
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-n-butylimidazole
The procedure of example 1 is repeated except that
2-n-butyl-4-imidazolealdehyde is used in place of
2-ethyl-4-imidazolealdehyde. M.p. of the base
152.degree.-156.degree. C.
EXAMPLE 3
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-2-methylimidazole
The procedure of example 1 is repeated except that
2-methyl-4-imidazolealdehyde and 2,6-dimethylphenylbromomethane are
used as starting materials.
.sup.1 H-NMR:2.27 (s, 6H), 2.35 (s, 3H), 3.16 (m, 2H), 4.68 (m,
2H), 6.65 (s, 1H), 6.98 (s, 3H)
EXAMPLE 4
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-phenylimidazole
The procedure of example 1 is repeated except that
2-phenyl-4-imidazolealdehyde is used. M.p. of the base is
181.degree.-183.degree. C.
.sup.1 H-NMR: 2.37 (s, 6H), 4.96 (s, 1H+H.sub.2 O), 6.34 (d, 1H),
6.80 (d, 1H), 7.02 (s, 3H), 7.35 (m, 3H), 7.86 (m, 2H)
EXAMPLE 5
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-methylimidazole
The procedure of example 1 is repeated except that
2-methyl-4-imidazolealdehyde is used. M.p. of the base is
176.degree.-177.degree. C.
EXAMPLE 6
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-2-methylimidazole
The procedure of example 1 is repeated except that
2-methyl-4-imidazolealdehyde and 2,3-dimethyl-1-bromobenzene are
used as starting materials. M.p. of the base is
176.degree.-178.degree. C.
According to the same method, for example the following compounds
were prepared:
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-2-ethylimidazole, M.p.
of the base 186.degree.-187.degree. C.
4-[4-(2'-chlorophenyl)-1-hydroxybutyl]-2-methylimidazole, M.p. of
the hydrochloride 134.degree.-136.degree. C.
4-[4-(2',6'-dichlorophenyl)-1-hydroxybutyl]-2-methylimidazole, M.p.
(hydrochloride) 150.degree.-151.degree. C.
4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-2-methylimidazole,
M.p. (base) 112.degree.-115.degree. C.
4-[6-(2',6'-dimethylphenyl)-1-hydroxyhexyl]-imidazole, M.p.
(hydrochloride) 106.degree.-111.degree. C.
4-[6-(2',6'-dimethylphenyl)-1-hydroxyhexyl]-2-methylimidazole
.sup.13 C-NMR (peaks ppm): 13.521, 19.969, 26.689, 30.322, 30.534,
31.079, 38.079, 38.102, 68,495, 117.234, 126.346, 128.980, 136.639,
140.392, 141.179, 145.539
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-benzylimidazole,
M.p. of the base 129.degree.-130,5.degree. C.
.sup.1 H-NMR: 1.74 (s, 3H), 2.21 (s, 3H), 5.17 (q, 2H), 5.67 (s,
1H), 6.3 (s, 1H), 7.0-7.4 (m, 9H)
.sup.13 C-NMR: 14.38, 20.37, 49.07, 64.72, 123.75, 125.42, 127.05,
127.99, 128.84, 128.84, 129,20, 129.32, 133.44, 136.26, 136.62,
138.80, 139.22
4-[.alpha.-(3'-methylphenyl)hydroxymethyl]-3-benzylimidazole, M.p.
of the base 128.degree.-131.degree. C.
.sup.1 H-NMR: 2.25 (s, 3H), 5.02 (q, 2H), 5.59 (s, 1H), 6.50 (s,
1H), 6.9-7.3 (m, 9H), 7.22 (d, 1H)
4-[.alpha.-(benzyl)hydroxymethyl]-3-benzylimidazole, M.p. of the
base 156.degree.-160.degree. C.
.sup.1 H-NMR: 3.06 (d, 2H), 4.72 (t, 1H), 5.07 (s, 2H), 6.9-7.4 (m,
12H)
4-[.alpha.-(4'-chlorophenyl)hydroxymethyl]-3-benzylimidazole, M.p.
of the base 160.degree.-163.degree. C.
.sup.1 H-NMR: 5.12 (q, 2H), 5.61 (s, 1H), 6.54 (s, 1H), 6.9-7.4 (m,
10H)
4-(3-phenyl-1-hydroxypropyl)-3-benzylimidazole, M.p. of the base
147.degree.-151.degree. C.
.sup.1 H-NMR: 1.9-2.3 (m, 2H), 2.5-2.8 (m, 2H), 4.48 (t, 1H), 5.16
(s, 2H), 6.92 (s, 1H), 7.00-7.35 (m, 10H), 7.37 (s, 1H)
4-[3-(3',4'-dimethylphenyl)-1-hydroxypropyl]-3-benzylimidazole,
M.p. of the hydrochloride 152.5.degree.-155.degree. C.
.sup.1 H-NMR (hydrochloride): 1.9-2.2 (m, 2H), 2.19 (s, 6H),
2.55-2.75 (m, 2H), 4.60 (t, 1H), 4.95 (s, 2H), 5.48 (s, 2H),
6.75-7.10 (m, 3H), 7.1-7.5 (m, 5H), 7.54 (s, 1H), 8.99 (s, 1H)
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-(4'-chlorobenzyl)-imidazo
le, M.p. of the hydrochloride 204.degree.-209.degree. C.
.sup.1 H-NMR (hydrochloride): 1.87 (s, 3H), 2.26 (s, 3H), 4.57 (s,
2H), 5.54 (s, 2H), 5.86 (s, 1H), 6.74 (s, 1H), 7.1-7.5 (m, 7H),
9.08 (d, 1H)
4-[.alpha.-(3'-methylphenyl)hydroxymethyl]-3-(4'-chlorobenzyl)-imidazole,
M.p. of the hydrochloride 179.degree.-182.degree. C.
.sup.1 H-NMR: 2.31 (s, 3H), 4.55 (broad signal, 2H), 5.41 (s, 2H),
5.78 (s, 1H), 6.98 (s, 1H), 7.0-7.4 (m, 8H), 8.86 (d, 1H)
4-(2-phenyl-1-hydroxyethyl)-3-(4'-chlorobenzyl)-imidazole, M.p. of
the base 184.degree.-188.degree. C.
.sup.1 H-NMR: 3.04 (d, 2H), 4.36 (s, 2H), 4.70 (t, 1H), 5.21 (s,
2H), 6.9-7.4 (m, 10H), 7.66 (s, 1H)
4-[.alpha.-(4'-chlorophenyl)hydroxymethyl]-3-(4'-chlorobenzyl)-imidazole,
M.p. of the hydrochloride 189.degree.-195.degree. C.
.sup.1 H-NMR (hydrochloride): 4.58 (board signal, 2H), 5.47 (s,
2H), 5.84 (s, 1H), 6.97 (q, 1H), 7.2-7.5 (m, 8H), 8.90 (s, 1H)
4-(3-phenyl-1-hydroxypropyl)-3-(4'-chlorobenzyl)-imidazole, M.p. of
the base 135.degree.-137.degree. C.
.sup.1 H-NMR: 1.9-2.3 (m, 2H), 2.6-2.8 (m, 2H), 4.42 (t, 1H), 5.10
(s, 2H), 6.85 (d, 1H), 6.9-7.3 (m, 10H)
4-[3-(3',4'-dimethylphenyl)-1-hydroxypropyl]-3-(4'-chlorobenzyl)imidazole,
M.p. of the base 126.degree.-130.degree. C.
.sup.1 H-NMR: 1.8-2.3 (m, 2H), 2.20 (s, 6H), 2.5-2.8 (m, 2H), 4.35
(broad signal, 1H), 5.11 (s, 2H), 6.7-7.4 (m, 9H)
4-[.alpha.-(2',3'-dimethylphenyl)hydroxymethyl]-3-(4'-methylbenzyl)-imidazo
le, M.p. of the hydrochloride 185.degree.-190.degree. C.
.sup.1 H-NMR: 1.78 (s, 3H), 2.20 (s, 3H), 2.33 (s, 3H), 5.42 (s,
2H), 5.6 (board signal, 1H), 5.99 (s, 1H), 6.63 (s, 1H), 7.0-7.4
(m, 7H), 8.72 (d, 1H)
4-[.alpha.-(3'-methylphenyl)hydroxymethyl]-3-(4'-methylbenzyl)-imidazole,
M.p. of the hydrochloride 152.degree.-155.degree. C.
.sup.1 H-NMR (hydrochloride): 2.30 (s, 3H), 2.33 (s, 3H), 5.1
(board signal, 1H), 5.31 (s, 2H), 5.85 (s, 1H), 6.96 (s, 1H), 7.12
(s, 8H), 8.52 (s, 1H)
4-(2-phenyl-1-hydroxyethyl)-3-(4'-methylbenzyl)-imidazole, M.p. of
the base 177.degree.-180.degree. C.
.sup.1 H-NMR: 2.33 (s, 3H), 3.08 (d, 2H), 4.75 (t, 1H), 5.04 (s,
2H), 6.8-7.5 (m, 10H)
4-[.alpha.-(4'-chlorophenyl)hydroxymethyl]-3-(4'-methylbenzyl)-imidazole,
M.p. of the hydrochloride 199.degree.-202.degree. C.
.sup.1 H-NMR: 2.34 (s, 3H), 4.89 (s, 2H), 5.43 (s, 2H), 5.88 (d,
1H), 7.17 (s, board, 5H), 7.35 (s, 4H), 8.90 (d, 1H)
4-(3-phenyl-1-hydroxypropyl)-3-(4'-methylbenzyl)-imidazole, M.p. of
the hydrochloride 156.degree.-159.degree. C.
.sup.1 H-NMR: 1.8-2.3 (m, 2H), 2.3 (s, 3H), 2.5-2.8 (m, 2H),
4.5-4.8 (m, 1H), 5.42 (s, 2H), 7.0-7.4 (m, 10H), 8.7 (d, 1H)
4-[3-(3',4'-dimethylphenyl)-1-hydroxypropyl]-3-(4'-methylbenzyl)imidazole,
M.p. of the hydrochloride 159.degree.-163.degree. C.
.sup.1 H-NMR: 1.8-2.3 (m, 2H), 2.23 (s, 6H), 2.35 (s, 3H), 2.5-2.7
(m, 2H), 4.5 (broad signal, 1H), 4.6-4.7 (m, 1H), 5.40 (s, 2H),
6.7-7.4 (m, 8H), 8.74 (d, 1H)
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-3-benzylimidazole,
M.p. of the hydrochloride 148.degree.-151.degree. C.
.sup.1 H-NMR: 1.75-2.10 (m, 2H), 2.24 (s, 6H), 2.6-3.0 (m, 2H),
4.74 (t, 1H), 4.94 (s, 2H), 5.57 (s, 2H), 6.93 (s, 3H), 7.37 (s,
5H), 7.56 (s, 1H), 9.01 (d, 1H)
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-3-benzylimidazole, M.p.
of the base 184.degree.-187.degree. C.
.sup.13 C-NMR: 20.19 (2C), 37.42, 49.28, 65.33, 126.63, 127.08,
127.48, 128.57, 128.87, 129.48, 135.35, 135.89, 137.13, 138.01,
138.83
4-[3-(2',6'-dimethyl)-1-hydroxypropyl]-3-ethylimidazole, M.p. of
the hydrochloride 178.degree.-179.degree. C.
.sup.13 C-NMR (hydrochloride): 15.76, 19.95 (2C), 26.70, 36.00,
43.84, 64.67, 117.66, 126.78, 129.08, 136.23, 136.96, 138.60,
139.00
4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-3-ethylimidazole. M.p.
of the hydrochloride 117.degree.-120.degree. C.
.sup.13 C-NMR (hydrochloride): 15.77, 19.95 (2C), 27.215, 30.03,
30.45, 36.45, 43.80, 64.60, 117.70, 126.42, 128.96, 136.20, 136.68,
138.71. 140.10
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-3-ethylimidazole. M.p.
of the base 185.degree.-189.degree. C.
.sup.1 H-NMR: 1.28 (t, 3H), 2.23 (s, 6H), 2.8-3.4 (m, 2H), 3.91 (q,
2H), 4.6-4.85 (m, 1H), 6.85 (s, 1H), 6.97 (s, 3H), 7.58 (s, 1H)
EXAMPLE 7
4-(2',6'-dimethylbenzyl)-2-ethylimidazole
5.0 g of
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-ethylimidazole
are dissolved in 50 ml of 4N HCl solution. About 0.5 g of 10%
palladium-on-carbon (Pd/C) are added and the mixture is stirred
vigorously under a hydrogen atmosphere at about 50.degree. C. until
no more hydrogen is consumed (about 4 hours). The catalyst is
filtered off, the solution is made alkaline after which the product
is filtered off and washed with water. Thus 4.3 g of crude base is
obtained. Its melting point is 160.degree.-163.degree. C. The base
may be converted into the hydrochloride in
isopropanol-HCl-ethylacetate. M.p. of the hydrochloride is
198.degree.-203.degree. C.
.sup.1 H-NMR: 1.51 (t, 3H), 2.38 (s, 6H), 3.11 (q, 2H), 4.14 (s,
2H), 6.71 (s, 1H), 7.22 (s, 3H)
.sup.13 C-NMR: 12.99 (q, 1C), 21.34 (q, 2C+t, 1C), 26.82 (t, 1C),
116.76 (d, 1C), 129.57 (s, 2C), 130.47 (d, 2C), 133.68 (s, 1C),
135.35 (s, 1C), 139.56 (d, 1C), 151.03 (s, 1C)
EXAMPLE 8
4-(2',6'-dimethylbenzyl)-2-n-butylimidazole
The procedure of example 7 is repeated except that
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-n-butylimidazole
is used. M.p. of the hydrochloride is 109.degree.-116.degree.
C.
.sup.1 H-NMR: 0.7-1.8 (m, 7H), 2.26 (s, 6H), 2.9 (t, 2H), 3.99 (s,
2H), 6.66 (s, 1H), 7.08 (s, 3H)
In the same way was prepared for example the compound
4-[3-(2',6'-dimethylphenyl)propyl]-2-ethylimidazole, M.p. of the
base 56.degree.-61.degree. C.
EXAMPLE 9
4-[2-(2',6'-dimethylphenyl)ethenyl]-2-methylimidazole
2.6 g of
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-2-methylimidazole is
mixed with 13.0 g of anhydrous potassium hydrogen sulfate and the
mixture is warmed at 140.degree. C. for 8 hours. The mixture is
then cooled and methanol is added. The mixture is stirred and
filtered. The product (base) is extracted in chloroform (pH 12),
washed with water and dried over Na.sub.2 SO.sub.4. The product
obtained (2.2 g) is the crude base, which may be converted to the
hydrochloride with HCl-ethylacetate is diisopropylether. The yield
is 0.7 g. M.p. of the hydrochloride is 194.degree.-197.degree.
C.
.sup.1 H-NMR: 2.43 (s, 6H), 2.72 (s, 3H), 6.48 (d, 1H), 7.15 (s,
3H), 7.25 (d, 1H), 7.28 (s, 1H)
According to the same method, for example the following compounds
were prepared:
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-2-ethylimidazole, M.p. of
the hydrochloride 165.degree.-172.degree. C.
4-[4-(2'-chlorophenyl)-1-butenyl]-2-methylimidazole, M.p. of the
hydrochloride 171.degree.-174.degree. C.
4-[4-(2',6'-dichlorophenyl)-1-butenyl]-2-methylimidazole, M.p. of
the hydrochloride 197.degree.-200.degree. C.
4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-2-methylimidazole
.sup.13 C-NMR (hydrochloride): 12.745, 21.493, 29.939, 31.029,
34.904, 115.883, 116.912, 127.416, 129.929, 132.411, 135.983,
137.558, 140.827, 146.579
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-imidazole, M.p. of the
hydrochloride 183.degree.-189.degree. C.
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-2-methylimidazole
.sup.13 C-NMR (hydrochloride): 12.714, 21.463, 30.780, 30.787,
30.150, 34.420, 115.822, 116.549, 127.265, 129.838, 132.381,
136.165, 137.255, 140.918, 146.549
4-[2-(2',6'-dimethylphenyl)ethenyl]-3-benzylimidazole, M.p. of the
hydrochloride 210.degree.-218.degree. C.
.sup.1 H-NMR (hydrochloride): 1.92 (s, 2H), 5.69 (s, 2H), 6.06 (d,
1H), 6.82 (s, 2H), 7.0-7.2 (m, 3H), 7.39 (s, 5H), 9.50 (d, 1H)
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-3-benzylimidazole, M.p. of
the hydrochloride 176.degree.-180.degree. C.
.sup.13 C-NMR: 19.34 (2C), 32.30, 49.31, 113.28, 115.58, 126.08,
127.21, 127.81, 128.11, 128.72, 131.84, 134.44, 135.05, 135.44,
135.71, 131.11
4-[2-(2',6'-dimethylphenyl)ethenyl]-3-ethylimidazole, M.p. of the
hydrochloride 140.degree.-148.degree. C.
.sup.13 C-NMR (hydrochloride): 15.74, 19.92, 21.13, 43.59, 115.64,
116.91, 117.79, 128.78, 129.02, 129.08, 135.85, 136.62, 137.19
4-[3-(2',6'-dimethylphenyl)-1-propenyl]-3-ethylimidazole, M.p. of
the hydrochloride 182.degree.-186.degree. C.
.sup.13 C-MNR (hydrochloride): 15.41, 20.04, 33.66, 43.38, 113.95,
116.61, 127.63, 129.20, 134.17, 135.26, 135.74, 137.71, 138.25
4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-3-ethylimidazole, M.p. of
the hydrochloride 165.degree.-169.degree. C.
.sup.13 C-MNR (hydrochloride): 15.56, 19.95, 29.30, 30.03, 34.39,
43.41, 114.34, 116.28, 126.57, 129.02, 134.41, 135.41, 136.74,
139.77, 140.74
4-[6-(2',6'-dimethylphenyl)-1-hexenyl]-5-methylimidazole
EXAMPLE 10
4-[2-(2',6'-dimethylphenyl)ethyl]-2-methylimidazole
The product is prepared by hydrogenation of
4-[2-(2',6'-dimethylphenyl)ethenyl]-2-methylimidazole in 80%
ethanol using 9,8% palladium-on-carbon. The product is isolated as
base into chloroform. The base is converted to the hydrochloride in
isopropanol-ethylacetate. M.p. of the hydrochloride
198.degree.-204.degree. C.
.sup.1 H-NMR: 2.36 (s, 6H), 2.73 (s, 3H), 2.92 (m, 4H), 7.09 (s,
1H), 7.13 (s, 3H)
According to the same method for example the following compounds
were prepared:
4-[5-(2',6'-dimethylphenyl)pentyl]-3-ethylimidazole, M.p. of the
hydrochloride 149.degree.-155.degree. C.
.sup.13 C-MNR (hydrochloride): 15.44, 19.98, 24.127, 28.456, 29.94,
30.36, 30.52, 43.02, 117.31, 126.45, 128.99, 135.20, 136.47,
136.68, 140.10
4-[2-(2',6'-dimethylphenyl)ethyl]-3-ethylimidazole, M.p. of the
hydrochloride 192.degree.-200.degree. C.
.sup.13 C-MNR (hydrochloride): 15.38, 19.89, 23.67, 28.73, 43.14,
117.91, 127.48, 129.32, 135.32, 135.98, 137.19, 137.56
4-[3-(2',6'-dimethylphenyl)propyl]-3-ethylimidazole, M.p. of the
hydrochloride 195.degree.-197.degree. C.
.sup.13 C-MNR (hydrochloride): 15.41, 19.98, 24.31, 28.15, 29.85,
43.05, 117.43, 126.84, 129.11, 135.29, 136.26, 136.89, 139.01
EXAMPLE 11
4-(2',6'-dimethylbenzyl)-2-methylimidazole
The procedure of example 7 is repeated except that
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-2-methylimidazole
is used.
M.p. of the base 162.degree.-165.degree. C.
M.p. of the hydrochloride 205.degree.-208.degree. C.
EXAMPLE 12
4-(2',6'-dimethylbenzyl)-3-methylimidazole and
4-(2',6'-dimethylbenzyl)-1-methylimidazole
3.0 g of 4-(2',6'-dimethylbenzyl)-imidazole, 40 ml of toluene, 3.0
g of methyliodide, 0.14 g of tetrabutylammoniumhydrogensulfate and
40 ml of 48% sodium hydroxide are mixed. The mixture is stirred
vigorously for 2 hours at 70.degree. C., after which the mixture is
cooled and filtered. The toluene layer is separated from the mother
liquid, after which it is washed with water and evaporated to
dryness. The residue is a mixture of
4-(2',6'-dimethylbenzyl)-3-methylimidazole and
4-(2',6'-dimethylbenzyl)-1-methylimidazole. These two components
are separated column chromatographically, eluting the column with a
mixture of chloroform and methanol.
4-(2',6'-dimethylbenzyl)-3-methylimidazole:
.sup.1 H-NMR: 2.250 (s, 6H), 3.632 (s, 3H), 3.810 (s, 2H), 6.201
(s, 1H), 7.067 (s, 3H), 7.395 (s, 1H)
4-(2',6'-dimethylbenzyl)-1-methylimidazole:
.sup.1 H-NMR: 2.305 (s, 6H), 3.490 (s, 3H), 3.933 (s, 2H), 6.136
(s, 1H), 7.017 (s, 3H), 7.300 (s, 1H)
According to the same method, for example the following compounds
were prepared:
4-[2-(2',6'-dimethylbenzyl)ethyl]-1-methylimidazole
.sup.13 C-MNR (hydrochloride): 19.859, 24.914, 29.516, 36.236,
120.669, 127.356, 129.263, 135.499, 135.988, 137.134, 137.588
4-[2-(2',6'-dimethylphenyl)ethyl]-3-methylimidazole
.sup.13 C-MNR (hydrochloride): 19.828, 23.219, 28.062, 33.754,
117.124, 127.083, 128.900, 128.900, 135.529, 135.681, 136.438
EXAMPLE 13
4-(2',6'-dimethylbenzyl)-3-tert.butylimidazole
4.44 g of 2,6-dimethylphenylacetaldehyde, 4.39 g of
tert.butylamine, 100 ml of methanol and 5.86 g of tosylmethyl
isocyanide are mixed. The mixture is stirred in room temperature
for 1 hour after which it is refluxed for 3 hours. The mixture is
evaporated to dryness, suspended in ether and filtered. The
filtrate is dissolved in chloroform and washed with 2M-hydrochloric
acid. The chloroform is evaporated to dryness and the residue is
crystallized from ethyl acetate. The hydrochloride obtained (3 g)
can be recrystallized from isopropanol. 2 g of product are obtained
and it melts at 235.degree.-237.degree. C.
.sup.1 H-NMR (hydrochloride): 1.85 (s, 9H), 2.20 (s, 6H), 4.05 (s,
2H), 6.70 (s, 1H), 7.05 (s, 3H), 9.15 (s, 1H).
According to the same method, for example the following compounds
were prepared:
4-(2',6'-dimethylbenzyl)-3-ethylimidazole, M.p. of the
hydrochloride 221.degree.-224.degree. C.
4-(2',6'-dimethylbenzyl)-3-methylimidazole, M.p. of the
hydrochloride 208.degree.-214.degree. C.
EXAMPLE 14
4-(2',6'-dimethylbenzyl)-1-(2'-chlorobenzyl)-imidazole
4-(2',6'-dimethylbenzyl)-3-(2'-chlorobenzyl)-imidazole
3.7 g of 4(5)-(2',6'-dimethylbenzyl)imidazole, 3.2 g of
2-chlorobenzylchloride, 0.2 g of
tetrabutylammonium-hydrogensulfate, 5,8 g of 48% NaOH and 40 ml of
toluene were mixed. The mixture was then stirred vigorously at
70.degree. C. as long as the starting compound,
4(5)-(2',6'-dimethylbenzyl)imidazole could be detected by using
thin layer chromatogrophic methods. The reaction mixture was cooled
and filtered. The toluene layer was separated and extracted
(3.times.20 ml of 1N HCl solution). The separated oil was extracted
to methylene chloride which then was washed with 5% NaHCO.sub.3
-solution and water, and finally evaporated to dryness.
The residue is a mixture of the isomeric products. The components
were separated through fractional recrystallization from
ethylacetate. The hydrochlorides of the products were prepared in
ethylacetate adding dry HCl-ethylacetate.
4-(2',6'-dimethylbenzyl)-1-(2'-chlorobenzyl)-imidazole. M.p. of the
hydrochloride 231.degree.-234.degree. C.
.sup.1 H-NMR (HCl-salt): 2.029 (s, 6H), 3.716 (s, 2H), 5.771 (s,
2H), 6.374 (s, 1H), 7.041 (m, 3H), 7.290-7.412 (m, 4H), 9.670 (s,
1H), 15.61 (broad band, 1H)
4-(2',6'-dimethylbenzyl)-3-(2'-chlorobenzyl)-imidazole. M.p. of the
hydrochloride 216.degree.-220.degree. C.
.sup.1 H-NMR (HCl): 2.231 (s, 6H), 4.155 (s, 2H), 5.493 (s, 2H),
6.295 (s, 1H), 7.068 (m, 3H), 7.068-7.52 (m, 5H), 9.678 (s, 1H)
According to the same method, for example the following compounds
were prepared:
4-[2-(2',6'-dimethylbenzyl)ethyl]-1-(4'-methylbenzyl)-imidazole,
M.p. of the hydrochloride 216.degree.-219.degree. C.
.sup.13 C-NMR (HCl-salt): 19.889, 21.160, 24.006, 28.547, 52.734,
116.488, 126.206, 128.173, 128.627, 129.899, 130.413, 134.682,
134.773, 136.195, 136.347, 139.162
4-[2-(2',6'-dimethylphenyl)ethyl]-3-(4'-methylbenzyl)-imidazole,
M.p. of the hydrochloride 180.degree.-183.degree. C.
.sup.13 C-NMR (HCl-salt): 19.647, 21.100, 23.007, 27.941, 50.434,
117.033, 126.781, 127.477, 128.536, 126.778, 130.050, 134.137,
135.106, 135.923, 135.983, 139.162
4-(2',3'-dimethylbenzyl)-1-(4'-methylbenzyl)-imidazole
.sup.1 H-NMR (HCl-salt): 2.149 (s, 3H), 2.266 (s, 3H), 2.332 (s,
3H), 4.001 (s, 2H), 5.057 (s, 2H), 6.46 (s, 1H), 7.037-7.259 (m,
8H), 8.20 (s, 1H)
4-(2',3'-dimethylbenzyl)-3-(4'-methylbenzyl)-imidazole. M.p. of the
hydrochloride 216.degree.-219.degree. C.
4-(2',6'-dimethylbenzyl)-1-(3'-methylbenzyl)-imidazole, M.p. of the
hydrochloride 210.degree.-212.degree. C.
4-(2',6'-dimethylbenzyl)-3-(4'-methylbenzyl)-imidazole
.sup.1 H-NMR (HCl-salt): 1.995 (s, 6H), 2.304 (s, 3H), 3.685 (s,
2H), 5.643 (s, 2H), 6.382 (s, 1H),.about.6.9-7.3 (m, 8H), 9.889 (s,
1H)
4-[2-(2',6'-dimethylphenyl)ethyl]-1-(2'-methylbenzyl)-imidazole.
M.p. of the hydrochloride 215.degree.-217.degree. C.
.sup.1 H-NMR (HCl): 2.257 (s, 6H), 2.306 (s, 3H), 2.956 (board m,
4H), 5.492 (s, 2H), 6.482 (s, 1H), 6.951 (s, 3H), 7.250 (m, 5H),
9.724 (s, 1H)
4-[2-(2',6'-dimethylphenyl)ethyl]-1-(2',6'-dichlorobenzyl)-imidazole.
M.p. of the base 140.degree.-142.degree. C.
.sup.1 H-NMR: 2.287 (s, 6H), 2.800 (m, 4H), 5.325 (s, 2H), 6.680
(s, 1H), 6.956 (s, 3H), 7.322 (m, 3H), 7.582 (s, 1H)
4-(2',3'-dimethylbenzyl)-1-(2',6'-dichlorobenzyl)-imidazole. M.p.
of the hydrochloride 238.degree.-241.degree. C.
.sup.1 H-NMR: 2.134 (s, 3H), 2.266 (s, 3H), 4.118 (s, 2H), 5.618
(s, 2H), 6.618 (s, 1H), 7.064 (s, 3H), 7.397 (s, 3H), 9.020 (s,
1H)
4-(2',3'-dimethylbenzyl)-3-(2',6'-dichlorobenzyl)-imidazole
.sup.1 H-NMR (HCl): 2.138 (s, 3H), 2.313 (s, 3H), 4.062 (s, 2H),
5.518 (s, 2H), 6.851 (s, 1H),.about.7.1 (m, 3H), 7.461 (s, 3H),
8.480 (s, 1H)
4-[2-(2',6'-dimethylphenyl)ethyl]-1-benzyl-imidazole. M.p.
202.degree.-207.degree. C.
.sup.1 H-NMR (hydrochloride): 2.14 (s, 6H), 2.5-3.1 (m, 4H), 4.91
(s, 1H), 5.32 (s, 2H), 6.97 (s, 3H), 7.1-7.5 (m, 6H), 8.99 (d,
1H)
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-3-(2'-chlorobenzyl)-imidazo
le. M.p. of the hydrochloride 139.degree.-142.degree. C.
.sup.1 H-NMR: 2.059 (s, 3H), 2.213 (s, 3H), 5.426 (s, 2H), 6.192
(s, 1H), 6.484 (s, 1H), 7.024-7.474 (m, 7H), 9.354 (s, 1H)
4-[.alpha.-(2',6'-dimethylphenyl)hydroxymethyl]-3-(3'-chlorobenzyl)-imidazo
le. M.p. of the hydrochloride 202.degree.-205.degree. C.
.sup.1 H-NMR (HCl): 2.249 (s, 6H), 2.309 (s, 3H), 5.240 (s, 2H),
6.324 (s, 1H), 6.499 (s, 1H), 7.003-7.173 (m, 7H), 9.155 (s,
1H)
* * * * *