U.S. patent application number 12/765898 was filed with the patent office on 2010-08-12 for imidazole derivatives.
Invention is credited to Guido Galley, Katrin Groebke Zbinden, Roger Norcross, Henri Stalder.
Application Number | 20100204233 12/765898 |
Document ID | / |
Family ID | 39153757 |
Filed Date | 2010-08-12 |
United States Patent
Application |
20100204233 |
Kind Code |
A1 |
Galley; Guido ; et
al. |
August 12, 2010 |
IMIDAZOLE DERIVATIVES
Abstract
The invention relates to imidazole derivatives which have a good
affinity to the trace amine associated receptors (TAARs),
especially for TAAR1. The invention also relates to a
pharmaceutically-suitable acid-addition salt of the above compound.
The invention further relates to a composition comprising an
imidazole derivative as described above, or a
pharmaceutically-suitable acid-addition salt thereof, and to
processes for preparing such compounds.
Inventors: |
Galley; Guido; (Rheinfelden,
DE) ; Groebke Zbinden; Katrin; (Liestal, CH) ;
Norcross; Roger; (Olsberg, CH) ; Stalder; Henri;
(Basel, CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
39153757 |
Appl. No.: |
12/765898 |
Filed: |
April 23, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11950449 |
Dec 5, 2007 |
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12765898 |
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Current U.S.
Class: |
514/235.8 ;
514/396; 514/397; 514/400; 544/139; 548/311.4; 548/341.1;
548/342.1; 548/343.1; 548/346.1 |
Current CPC
Class: |
A61P 3/06 20180101; A61P
25/14 20180101; A61P 25/00 20180101; A61P 25/06 20180101; A61P 3/04
20180101; A61P 25/16 20180101; A61P 25/22 20180101; A61P 9/00
20180101; A61P 25/30 20180101; A61P 25/18 20180101; A61P 25/24
20180101; A61P 25/28 20180101; C07D 233/64 20130101; A61P 3/10
20180101 |
Class at
Publication: |
514/235.8 ;
514/396; 514/397; 514/400; 544/139; 548/311.4; 548/341.1;
548/342.1; 548/343.1; 548/346.1 |
International
Class: |
A61K 31/4164 20060101
A61K031/4164; A61K 31/5377 20060101 A61K031/5377; A61K 31/4178
20060101 A61K031/4178; C07D 413/10 20060101 C07D413/10; C07D 405/12
20060101 C07D405/12; C07D 233/64 20060101 C07D233/64; C07D 233/58
20060101 C07D233/58; A61P 25/00 20060101 A61P025/00; A61P 25/22
20060101 A61P025/22; A61P 25/24 20060101 A61P025/24; A61P 25/16
20060101 A61P025/16 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2006 |
EP |
06126307.5 |
Claims
1. A compound according to formula I, ##STR00101## wherein R is
selected from the group consisting of hydrogen, lower alkyl and
amino; X is selected from the group consisting of --CH.sub.2--,
--CH(lower alkoxy)-, --CH(OH)--, and --NH--; Y is selected from the
group consisting of --CH.sub.2, --CH(lower alkyl)-, --CH(lower
alkoxy)-, --O--, --S--, --S(O)--, --S(O).sub.2--, --CH(phenyl)- and
--C(lower alkyl).sub.2-; and Ar is selected from the group
consisting of phenyl, napthtyl and benzofuranyl, said phenyl,
mapthyl, or benzofuranyl being unsubstituted or substituted by one
or more substituents, each substituent being independently selected
from the group consisting of lower alkyl, lower alkyl substituted
by halogen, halogen, lower alkoxy, lower alkoxy substituted by
halogen, hydroxy, amino, di-alkylamino, morpholinyl, phenyl, benzyl
and O-benzyl; or a pharmaceutically-suitable acid-addition salt
thereof; with the provisio that, wherein, when X is --NH--, Y is
selected from the group consisting of --CH.sub.2, --CH(lower
alkyl)-, --CH(lower alkoxy)-, --CH(phenyl)- or --C(lower
alkyl).sub.2-; and the further proviso that said compound is not
5-phenethyl-1H-imidazole, 5-(2-phenyl-propyl)-1H-imidazole,
1-(1H-imidazol-4-yl)-2-phenyl-ethanol,
5-(2,2-diphenyl-ethyl)-1H-imidazole,
4-(2-m-tolyl-ethyl)-1H-imidazole,
4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole,
4-(biphenyl-2-yloxymethyl)-1H-imidazole,
5-(2-methyl-2-phenyl-propyl)-1H-imidazole,
4-(2-chloro-phenoxymethyl)-1H-imidazole,
4-(2-fluoro-phenoxymethyl)-1H-imidazole,
4-o-tolyloxymethyl-1H-imidazole,
4-(3-chloro-phenoxymethyl)-1H-imidazole,
4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or
5-methyl-4-phenylsulfanylmethyl-1H-imidazole.
2. A compound according to claim 1, wherein X and Y are both
--CH.sub.2--.
3. A compound according to claim 2, selected from the group
consisting of: 4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole;
4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole;
4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole;
4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole;
4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;
4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole;
4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole;
4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
4. A compound according to claim 1, wherein X is --CH.sub.2-- and Y
is --CH(lower alkyl).
5. A compound according to claim 4, selected from the group
consisting of: 4-(2-phenyl-butyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
6. A compound according to claim 1, wherein X is --CH.sub.2-- and Y
is --O--.
7. A compound according to claim 6, selected from the group
consisting of: 4-(2,3-dichloro-phenoxymethyl)-1H-imidazole;
4-(2,3-difluoro-phenoxymethyl)-1H-imidazole;
4-(3,4-dichloro-phenoxymethyl)-1H-imidazole;
4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole;
5-(benzofuran-6-yloxymethyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
8. A compound according to claim 1, wherein X is --CH.sub.2-- and Y
is --S--.
9. A compound according to claim 8, selected from the group
consisting of: 5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole;
4-(4-chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole;
4-(naphthalen-2-ylsulfanylmethyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
10. A composition comprising a compound according to claim 1 and a
therapeutically-inert carrier.
11. A process for the preparation of a compound of formula I,
##STR00102## comprising deprotecting a compound according to
formula II, ##STR00103## wherein, in the above formulas, R is
selected from the group consisting of hydrogen, lower alkyl and
amino; X is selected from the group consisting of --CH.sub.2--,
--CH(lower alkoxy)-, --CH(OH)--, and --NH--; Y is selected from the
group consisting of --CH.sub.2, --CH(lower alkyl)-, --CH(lower
alkoxy)-, --O--, --S--, --S(O)--, --S(O).sub.2--, --CH(phenyl)- and
--C(lower alkyl).sub.2-; and Ar is selected from the group
consisting of phenyl, napthtyl and benzofuranyl, said phenyl,
mapthyl, or benzofuranyl being unsubstituted or substituted by one
or more substituents, each substituent being independently selected
from the group consisting of lower alkyl, lower alkyl substituted
by halogen, halogen, lower alkoxy, lower alkoxy substituted by
halogen, hydroxy, amino, di-alkylamino, morpholinyl, phenyl, benzyl
and O-benzyl; with the provisio that, wherein, when X is --NH--, Y
is selected from the group consisting of --CH.sub.2, --CH(lower
alkyl)-, --CH(lower alkoxy)-, --CH(phenyl)- or --C(lower
alkyl).sub.2-.
12. A compound according to claim 2 wherein said compound is
selected from the group consisting of:
4-[2-(2-ethyl-phenyl)-ethyl]-1H-imidazole;
4-[2-(2-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;
{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine;
4-{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-morpholine;
4-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-imidazole;
2-methyl-5-phenethyl-1H-imidazole;
5-phenethyl-1H-imidazol-2-ylamine; and pharmaceutically-suitable
acid-addition salts thereof.
13. A compound according to claim 3 wherein said compound is
selected from the group consisting of:
4-(3-methyl-2-phenyl-butyl)-1H-imidazole;
4-(3,3-dimethyl-2-phenyl-butyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
14. A compound according to claim 6 wherein said compound is
selected from the group consisting of:
4-(2-Ethyl-phenoxymethyl)-1H-imidazole;
4-(2-Isopropyl-phenoxymethyl)-1H-imidazole;
4-(2-Trifluoromethyl-phenoxymethyl)-1H-imidazole;
4-(2-Benzyl-phenoxymethyl)-1H-imidazole;
4-(2-Methoxy-phenoxymethyl)-1H-imidazole;
4-(2-Isopropoxy-phenoxymethyl)-1H-imidazole;
4-(2-Trifluoromethoxy-phenoxymethyl)-1H-imidazole;
4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole;
2-(1H-Imidazol-4-ylmethoxy)-phenol;
4-(3-Trifluoromethyl-phenoxymethyl)-1H-imidazole;
4-(3-Trifluoromethoxy-phenoxymethyl)-1H-imidazole;
[3-(1H-Imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine;
4-[-(1H-Imidazol-4-ylmethoxy)-phenyl]-morpholine;
4-(2,6-Diethyl-phenoxymethyl)-1H-imidazole;
4-(3,4-Difluoro-phenoxymethyl)-1H-imidazole;
4-(3-Chloro-5-fluoro-phenoxymethyl)-1H-imidazole;
5-(4-Bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
15. A compound according to claim 1 wherein X is --CH.sub.2-- and Y
is --S(O)--, said compound selected from the group consisting of:
4-benzenesulfinylmethyl-5-methyl-1H-imidazole;
5-(2,3-dichloro-benzenesulfinylmethyl)-1-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
16. A compound according to claim 1 wherein X is --CH.sub.2-- and Y
is --S(O).sub.2--, said compound selected from the group consisting
of: 5-(2,3-dichloro-benzenesulfonylmethyl)-1-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
17. A compound according to claim 1 wherein X is --NH-- and Y is
--CH.sub.2--, said compound selected from the group consisting of:
Benzyl-(1H-imidazol-4-yl)-amine; and pharmaceutically-suitable
acid-addition salts thereof.
18. A compound according to claim 1 wherein X is --CH(lower
alkoxy)- and Y is --CH.sub.2--, said compound selected from the
group consisting of: 4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. application Ser.
No. 11/950,449, filed Dec. 5, 2007, now pending; which claims the
benefit of European Patent Application No. 06126307.5, filed Dec.
18, 2006. The entire contents of the above-identified applications
are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to compounds which have a good
affinity to the trace amine associated receptors (TAARs),
especially for TAAR1.
[0003] These compounds are useful in the treatment or prevention
of, inter alia, disorders of the central nervous system, for
example, the treatment or prevention of depression, psychosis,
Parkinson's disease, anxiety and/or attention deficit hyperactivity
disorder (ADHD).
[0004] The invention relates also to processes for preparing such
compounds and a pharmaceutical composition comprising such a
compound.
BACKGROUND OF THE INVENTION
[0005] The classical biogenic amines (serotonin, norepinephrine,
epinephrine, dopamine, histamine) play important roles as
neurotransmitters in the central and peripheral nervous system.
Deutch, A. Y. and Roth R. H. (1990) Neurotransmitters. In
Fundamental Neuroscience (2nd ed.) (Zigmond, M. J., Bloom, F. E.,
Landis, S. C., Roberts, J. L., and Squire L. R., eds.) 193-234,
Academic Press. Their synthesis and storage, as well as their
degradation and reuptake after release are tightly regulated. An
imbalance in the levels of biogenic amines is known to be
responsible for the altered brain function under many pathological
conditions. Wong, M. L. and Licinio, J. (2001) Nat. Rev. Neurosci.
2, 343-351; Carlsson, A. et al. (2001), Annu. Rev. Pharmacol.
Toxicol. 41, 237-260; Tuite, P. and Riss, J. (2003), Expert Opin.
Investig. Drugs 12, 1335-1352; Castellanos, F. X. and Tannock, R.
(2002), Nat. Rev. Neurosci. 3, 617-628.
[0006] A second class of endogenous amine compounds, the so-called
trace amines (TAs) significantly overlap with the classical
biogenic amines regarding structure, metabolism and subcellular
localization. The TAs include p-tyramine, .beta.-phenylethylamine,
tryptamine and octopamine, and they are present in the mammalian
nervous system at generally lower levels than classical biogenic
amines. Usdin, E. and Sandler, M. eds. (1984), Trace Amines and the
brain, Dekker. Their disregulation has been linked to various
psychiatric diseases like schizophrenia and depression and for
other conditions like attention deficit hyperactivity disorder,
migraine headache, Parkinson's disease, substance abuse and eating
disorders. Lindemann, L. and Hoener, M. (2005), Trends in
Pharmacol. Sci. 26, 274-281; Branchek, T. A. and Blackburn, T. P.
(2003), Curr. Opin. Pharmacol. 3, 90-97; Premont, R. T. et al.
(2001), Proc. Natl. Acad. Sci. U.S.A. 98, 9474-9475.
[0007] For a long time, TA-specific receptors had only been
hypothesized based on anatomically discrete high-affinity TA
binding sites in the central nervous system of humans and other
mammals. Mousseau, D. D. and Butterworth, R. F. (1995), Prog. Brain
Res. 106, 285-291; McCormack, J. K. et al. (1986), J. Neurosci. 6,
94-101. Accordingly, the pharmacological effects of TAs were
believed to be mediated through the well known machinery of
classical biogenic amines, by either triggering their release,
inhibiting their reuptake or by "crossreacting" with their receptor
systems. Premont, R. T. et al. (2001), Proc. Natl. Acad. Sci.
U.S.A. 98, 9474-9475; Dyck, L. E. (1989), Life Sci. 44, 1149-1156;
Parker, E. M. and Cubeddu, L. X. (1988), J. Pharmacol. Exp. Ther.
245, 199-210. This view changed significantly with the recent
identification of several members of a novel family of GPCRs, the
trace amine associated receptors (TAARs). Lindemann, L. and Hoener,
M. (2005), Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L. et
al. (2005), Genomics 85, 372-385.
[0008] There are 9 TAAR genes in human (including 3 pseudogenes)
and 16 genes in mouse (including 1 pseudogene). The TAAR genes do
not contain introns (with one exception, TAAR2 contains 1 intron)
and are located next to each other on the same chromosomal segment.
The phylogenetic relationship of the receptor genes, in agreement
with an in-depth GPCR pharmacophore similarity comparison and
pharmacological data suggest that these receptors form three
distinct subfamilies. Lindemann, L. and Hoener, M. (2005), Trends
in Pharmacol. Sci. 26, 274-281; Lindemann, L. et al. (2005),
Genomics 85, 372-385. TAAR1 is in the first subclass of four genes
(TAAR1-4) highly conserved between human and rodents. TAs activate
TAAR1 via G.alpha.s. Disregulation of TAs was shown to contribute
to the aetiology of various diseases like depression, psychosis,
attention deficit hyperactivity disorder, substance abuse,
Parkinson's disease, migraine headache, eating disorders, metabolic
disorders and therefore TAAR1 ligands have a high potential for the
treatment of these diseases.
[0009] It has been found that the compounds of formula I (described
below) have a good affinity to the TAARs, especially for TAAR1.
[0010] The compounds as useful in the treatment or prevention of
depression, anxiety disorders, bipolar disorder, attention deficit
hyperactivity disorder (ADHD), stress-related disorders, psychotic
disorders such as schizophrenia, neurological diseases such as
Parkinson's disease, neurodegenerative disorders such as
Alzheimer's disease, epilepsy, migraine, hypertension, substance
abuse and metabolic disorders such as eating disorders, diabetes,
diabetic complications, obesity, dyslipidemia, disorders of energy
consumption and assimilation, disorders and malfunction of body
temperature homeostasis, disorders of sleep and circadian rhythm,
and/or cardiovascular disorders. Preferably, the compounds are
useful in the treatment or prevention of disorders of the central
nervous system, for example, the treatment or prevention of
depression, psychosis, Parkinson's disease, anxiety and/or
attention deficit hyperactivity disorder (ADHD).
SUMMARY OF THE INVENTION
[0011] The present invention is directed to a compound according to
formula I,
##STR00001##
wherein R is selected from the group consisting of hydrogen, lower
alkyl and amino; X is selected from the group consisting of
--CH.sub.2--, --CH(lower alkoxy)-, --CH(OH)--, and --NH--; Y is
selected from the group consisting of --CH.sub.2, --CH(lower
alkyl)-, --CH(lower alkoxy)-, --O--, --S--, --S(O)--,
--S(O).sub.2--, --CH(phenyl)- and --C(lower alkyl).sub.2-; and Ar
is selected from the group consisting of phenyl, napthtyl and
benzofuranyl, said phenyl, mapthyl, or benzofuranyl being
unsubstituted or substituted by one or more substituents, each
substituent being independently selected from the group consisting
of lower alkyl, lower alkyl substituted by halogen, halogen, lower
alkoxy, lower alkoxy substituted by halogen, hydroxy, amino,
di-alkylamino, morpholinyl, phenyl, benzyl and O-benzyl; with the
provisio that, wherein, when X is --NH--, Y is selected from the
group consisting of --CH.sub.2, --CH(lower alkyl)-, --CH(lower
alkoxy)-, --CH(phenyl)- or --C(lower alkyl).sub.2-; and the further
proviso that said compound is not [0012] 5-phenethyl-1H-imidazole,
[0013] 5-(2-phenyl-propyl)-1H-imidazole, [0014]
1-(1H-imidazol-4-yl)-2-phenyl-ethanol, [0015]
5-(2,2-diphenyl-ethyl)-1H-imidazole, [0016]
4-(2-m-tolyl-ethyl)-1H-imidazole, [0017]
4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole, [0018]
4-(biphenyl-2-yloxymethyl)-1H-imidazole, [0019]
5-(2-methyl-2-phenyl-propyl)-1H-imidazole, [0020]
4-(2-chloro-phenoxymethyl)-1H-imidazole, [0021]
4-(2-fluoro-phenoxymethyl)-1H-imidazole, [0022]
4-o-tolyloxymethyl-1H-imidazole, [0023]
4-(3-chloro-phenoxymethyl)-1H-imidazole, [0024]
4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or [0025]
5-methyl-4-phenylsulfanylmethyl-1H-imidazole.
[0026] The present invention also relates to a
pharmaceutically-suitable acid-addition salt of such a
compound.
[0027] The invention includes all racemic mixtures, all their
corresponding enantiomers and/or optical isomers.
[0028] In addition, all tautomeric forms of compounds of formula I
are also encompassed by the present invention.
[0029] The present invention is also directed to processes for the
preparation of the above compound.
[0030] The present invention is also directed to a pharmaceutical
composition comprising the above compound or a
pharmaceutically-suitable acid-addition salt thereof.
[0031] Compounds according to the present invention have a good
affinity to the TAARs, especially for TAAR1. Such compounds are
useful in the treatment or prevention of illnesses such as
depression, anxiety disorders, bipolar disorder, attention deficit
hyperactivity disorder, stress-related disorders, psychotic
disorders such as schizophrenia, neurological diseases such as
Parkinson's disease, neurodegenerative disorders such as
Alzheimer's disease, epilepsy, migraine, hypertension, substance
abuse and metabolic disorders such as eating disorders, diabetes,
diabetic complications, obesity, dyslipidemia, disorders of energy
consumption and assimilation, disorders and malfunction of body
temperature homeostasis, disorders of sleep and circadian rhythm,
and cardiovascular disorders. Preferably, the compounds of the
present invention are useful in the treatment or prevention of
disorders of the central nervous system, for example, the treatment
or prevention of depression, psychosis, Parkinson's disease,
anxiety and/or attention deficit hyperactivity disorder (ADHD).
DETAILED DESCRIPTION OF THE INVENTION
[0032] The present invention is directed to a compound according to
formula I,
##STR00002##
wherein R is selected from the group consisting of hydrogen, lower
alkyl and amino; X is selected from the group consisting of
--CH.sub.2--, --CH(lower alkoxy)-, --CH(OH)--, and --NH--; Y is
selected from the group consisting of --CH.sub.2, --CH(lower
alkyl)-, --CH(lower alkoxy)-, --O--, --S--, --S(O)--,
--S(O).sub.2--, --CH(phenyl)- and --C(lower alkyl).sub.2-; and Ar
is selected from the group consisting of phenyl, napthtyl and
benzofuranyl, said phenyl, mapthyl, or benzofuranyl being
unsubstituted or substituted by one or more substituents, each
substituent being independently selected from the group consisting
of lower alkyl, lower alkyl substituted by halogen, halogen, lower
alkoxy, lower alkoxy substituted by halogen, hydroxy, amino,
di-alkylamino, morpholinyl, phenyl, benzyl and O-benzyl; with the
provisio that, wherein, when X is --NH--, Y is selected from the
group consisting of --CH.sub.2, --CH(lower alkyl)-, --CH(lower
alkoxy)-, --CH(phenyl)- or --C(lower alkyl).sub.2-; and the further
proviso that said compound is not [0033] 5-phenethyl-1H-imidazole,
[0034] 5-(2-phenyl-propyl)-1H-imidazole, [0035]
1-(1H-imidazol-4-yl)-2-phenyl-ethanol, [0036]
5-(2,2-diphenyl-ethyl)-1H-imidazole, [0037]
4-(2-m-tolyl-ethyl)-1H-imidazole, [0038]
4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole, [0039]
4-(biphenyl-2-yloxymethyl)-1H-imidazole, [0040]
5-(2-methyl-2-phenyl-propyl)-1H-imidazole, [0041]
4-(2-chloro-phenoxymethyl)-1H-imidazole, [0042]
4-(2-fluoro-phenoxymethyl)-1H-imidazole, [0043]
4-o-tolyloxymethyl-1H-imidazole, [0044]
4-(3-chloro-phenoxymethyl)-1H-imidazole, [0045]
4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or [0046]
5-methyl-4-phenylsulfanylmethyl-1H-imidazole.
[0047] The present invention also relates to a
pharmaceutically-suitable acid-addition salt of such a
compound.
[0048] The invention includes all racemic mixtures, all their
corresponding enantiomers and/or optical isomers.
[0049] In addition, all tautomeric forms of compounds of formula I
are also encompassed by the present invention.
[0050] The present invention is also directed to processes for the
preparation of the above compound.
[0051] As used herein, the term "halogen" refers to chlorine,
iodine, fluorine or bromine.
[0052] As used herein, the term "lower alkyl" denotes a saturated
straight- or branched-chain hydrocarbon group containing from 1 to
7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl,
n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower
alkyl groups are groups with 1 to 4 carbon atoms.
[0053] As used herein, the term "lower alkyl substituted by
halogen" denotes a lower alkyl group as defined above, wherein at
least one hydrogen atom is replaced by halogen, for example
--CF.sub.3, --CHF.sub.2, --CH.sub.2F, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CF.sub.2CF.sub.3 and the
like.
[0054] As used herein, the term "lower alkoxy" denotes a
substituent wherein the alkyl residue is attached to the remainder
of the molecule via an oxygen group.
[0055] The term "pharmaceutically-suitable acid-addition salt"
embraces salts of a compound of formula I with inorganic and
organic acids, such as hydrochloric acid, nitric acid, sulfuric
acid, phosphoric acid, citric acid, formic acid, fumaric acid,
maleic acid, acetic acid, succinic acid, tartaric acid,
methane-sulfonic acid, p-toluenesulfonic acid and the like, the
salt not being toxic and not interfering with the ability of the
compound of formula I to elicit the biological or medical response
of a tissue system, animal or human, that is being sought by the
researcher, veterinarian, medical doctor or other clinician.
[0056] Preferred compounds of the present invention are those of
formula I wherein X and Y are both --CH.sub.2--. Such compounds
include: [0057] 4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole; [0058]
4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole; [0059]
4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole; [0060]
4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole; [0061]
4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole; [0062]
4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole; [0063]
4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole; [0064]
4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
[0065] Also preferred are compounds of the present invention are
those of formula I wherein X is --CH.sub.2-- and Y is --CH(lower
alkyl), for example the following compounds: [0066]
4-(2-phenyl-butyl)-1H-imidazole; and pharmaceutically-suitable
acid-addition salts thereof.
[0067] Additional preferred are compounds of the present invention
are those of formula I wherein X is --CH.sub.2-- and Y is --O--,
for example the following compounds: [0068]
4-(2,3-dichloro-phenoxymethyl)-1H-imidazole; [0069]
4-(2,3-difluoro-phenoxymethyl)-1H-imidazole; [0070]
4-(3,4-dichloro-phenoxymethyl)-1H-imidazole; [0071]
4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole; [0072]
5-(benzofuran-6-yloxymethyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
[0073] Yet another preferred embodiment of the present invention
are compounds of formula I, wherein X is --CH.sub.2-- and Y is
--S--, for example the following compounds: [0074]
5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole; [0075]
4-(4-chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole; [0076]
4-(naphthalen-2-ylsulfanylmethyl)-1H-imidazole; and
pharmaceutically-suitable acid-addition salts thereof.
[0077] The present compounds of formula I and their
pharmaceutically-suitable acid-addition salts can be prepared by
various processes, for example, by a process comprising
a) deprotecting a compound of formula
##STR00003##
to produce a compound of formula
##STR00004##
wherein the definitions are as described above, or b) hydrogenating
a compound of formula
##STR00005##
to produce a compound of formula
##STR00006##
and deprotecting the compound of formula II-1 in a step analogous
to step (a) to produce a compound of formula
##STR00007##
wherein Ar is as defined above and R.sup.2 is hydrogen, lower alkyl
or lower alkoxy, or c) alkylating a compound of formula
##STR00008##
to produce a compound of formula
##STR00009##
and deprotecting the compound of formula II-2 in a step analogous
to step (a) to produce a compound of formula
##STR00010##
wherein Ar is as defined above; or d) reacting a compound of
formula
##STR00011##
and a compound of formula
ArOH X
to produce a compound of formula
##STR00012##
and deprotecting the compound of formula II-3 in a step analogous
to step (a) to produce a compound of formula
##STR00013##
wherein the definitions are as described above, or e) reacting a
compound of formula
##STR00014##
with acetonitrile to produce a compound of formula
##STR00015##
and removing the hydroxy group to produce a compound of formula
##STR00016##
wherein Ar is as defined above, or reacting a compound of
formula
##STR00017##
with a compound of formula
##STR00018##
to produce a compound of formula
##STR00019##
and deprotecting to produce a compound of formula
##STR00020##
wherein R is lower alkyl and Ar is as described above, or g)
reacting a compound of formula
##STR00021##
and a compound of formula
ArSH X'
to produce a compound of formula
##STR00022##
and deprotecting the compound of formula II-4 in a step analogous
to step (a) to produce a compound of formula
##STR00023##
wherein Ar is as defined above, or h) oxidizing a compound of
formula
##STR00024##
to produce a compound of formulas
##STR00025##
and deprotecting said compound of formula II-5 or formula II-6 in a
step analogous to step (a) to produce a compound of formulas
##STR00026##
respectively, wherein Ar is as defined above; or i) reducing a
compound of formula
##STR00027##
to produce a compound of formula
##STR00028##
and deprotecting the compound of formula II-7 in a step analogous
to step (a) to produce a compound of formula
##STR00029##
wherein Ar is as described above and PG is a common N-protecting
group.
[0078] If desired, the above produced compounds of formula I may be
converted into pharmaceutically-suitable acid-addition salts.
[0079] The following are general schemes which exemplify the use of
the above processes in the production of compounds of formula I.
The starting materials are either commercially available (e.g.,
from one or more of the following chemical suppliers such as
Aldrich, Fluka, Acros, Maybridge, Avocado, TCI, or additional
suppliers as indicated in databases such as Chemical Abstracts
[American Chemical Society, Columbus, Ohio] or Available Chemicals
Director [Elsevier MDL, San Ramon, California]), are otherwise
known in the chemical literature, or may be prepared in accordance
with methods well known in the art.
Procedure A
Synthesis of C--C-Linked Compounds
##STR00030##
[0081] Step A: The Wittig reaction between an aldehyde or a ketone
of formula III and (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic
acid diethyl ester (IV) can be accomplished by using a base such as
NaH, KO-tert-butyl (KOtBu), NaOCH.sub.3, NaOCH.sub.2CH.sub.3,
n-butyllithium, LiHMDS, NaHMDS, KHMDS, and LDA in a solvent such as
tetrahydrofuran (THF), dioxane, acetonitrile, 1,2-dimethoxyethan,
DMF, benzene, toluene or mixtures thereof at temperatures from
-78.degree. C.-80.degree. C. for 15 minutes-8 hours and, if
appropriate, optional addition of a crown ether for ylide
generation and then condensing the ylide with the carbonyl compound
in the same solvent at a temperature between 0 and 80.degree. C.
for 1-24 hours. Alternatively, the base, the carbonyl compound and
the optional crown ether can be added to the reaction mixture at
the same time without preformation of the ylide at temperatures
from -78.degree. C.-80.degree. C.
[0082] Preferred conditions for reactions with aryl ketones are
ylide formation at room temperature using KOtBu as the base and THF
as the solvent, reacting the phosphonic acid ester for 15 minutes
at room temperature, and then condensation with the carbonyl
component at 80.degree. C. overnight. Preferred conditions for
benzaldehydes are ylide formation in the presence of the carbonyl
compound using KOtBu as the base and THF as the solvent at
80.degree. C. overnight.
[0083] Step B: The reduction of the alkene of formula V can be
effected by hydrogenation with hydrogen under normal or elevated
pressure or by transfer hydrogenation using ammonium formiate or
cyclohexadiene as a hydrogen source with a catalyst such as
PtO.sub.2, Pd--C or Raney nickel in solvents such as methanol
(MeOH), ethanol (EtOH), H.sub.2O, dioxane, THF, HOAc, EtOAc,
CH.sub.2Cl.sub.2, CHCl.sub.3, DMF or mixtures thereof.
Alternatively, the reduction of the alkene can be effected by Mg in
MeOH or by LiAlH.sub.4 in THF or diethylether.
[0084] The preferred procedure for trisubstituted alkenes is
hydrogenation at normal pressure in MeOH/CH.sub.2Cl.sub.2 using 10%
Pd/C as catalyst. The preferred procedure for disubstituted alkenes
is hydrogenation at normal pressure in MeOH/CHCl.sub.3/AcOH using
10% Pd/C as catalyst. Both conditions may lead to partial loss of
the trityl protecting group. In this case the mixture of protected
and unprotected products is subjected directly to conditions C.
[0085] Step C: The cleavage of the trityl group can be effected
with a mineral acid such as HCl, H.sub.2SO.sub.4 or H.sub.3PO.sub.4
or a organic acid such as CF.sub.3COOH, CHCl.sub.2COOH, HOAc or
p-toluonesulfonic acid in a solvent such as CH.sub.2Cl.sub.2,
CHCl.sub.3, THF, MeOH, EtOH or H.sub.2O at 0 to 60.degree. C.
[0086] Preferred conditions are 2N HCl in EtOH at reflux for 1-3
hours.
Procedure B
Synthesis of C--C-Linked Compounds with Alkoxy Substituent in
.alpha. Position to Imidazoles
##STR00031##
[0088] Step A: The formylation of
2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid
dimethyl-amide (VII) can be effected by deprotonation with a strong
base such as n-butyllithium, s-butyllithium or t-butyllithium and
optionally an additive such as tetramethylethylene diamine or
pentamethyl diethylene triamine in a solvent such as THF or
diethylether at -78.degree. C.--40.degree. C., followed by
quenching the anion with a formylating electrophile such as DMF at
-78.degree. to room temperature for 1-24 hours.
[0089] Preferred conditions are deprotonation with n-butyllithium
at -78.degree. C. for 10 minutes, then reaction with DMF at
-78.degree. C. for 2 hours.
[0090] Step B: The Grignard reaction of the protected formyl
imidazole (VII) with an aryl magnesium chloride or bromide (VIII)
can be effected by adding a solution of the Grignard reagent
(commercially available or prepared form a benzyl chloride or
bromide and Mg by standard methods) in a solvent such as
diethylether, THF or benzene to a solution of the aldehyde in one
of the previously mentioned solvents at -20.degree. C. to room
temperature and letting the two components react at room
temperature to reflux temperature for 1-24 hours.
[0091] Preferred conditions involve addition of the Grignard
reagent in diethylether to a solution of aldehyde in THF at room
temperature and reaction at room temperature overnight.
[0092] Step C: The alkylation of the alcohol of formula IX can be
accomplished by deprotonation of the hydroxy group with a base such
as NaH, KH, n-butyllithium, KOtBu, KOH or aqueous NaOH and KOH in
the presence of a phase transfer catalyst (tetraalkylammonium
salts) in a suitable solvent such as THF, DMF, DMSO, toluene or
1,2-dimethoxyethane at -78.degree. C. to room temperature for 30
minutes-2 hours and subsequent addition of an alkyl halide.
[0093] Preferred conditions are deprotonation with NaH in THF at
room temperature for 1 hour and alkylation with an alkyl iodide at
room temperature overnight.
[0094] Step D: The simultaneous cleavage of both protecting groups
(II-2) can be achieved in the presence of a mineral acid such as
HCl, HBr or H.sub.2SO.sub.4 in a solvent such as EtOH, MeOH,
H.sub.2O or THF at room temperature reflux temperature for 1-24
hours.
[0095] Preferred conditions are 2N HCl in EtOH at reflux for 1-3
hours.
Procedure C
Synthesis of C--O-Linked Compounds
##STR00032##
[0097] Step A: The alkylation of a substituted phenol with
4-chloromethyl-1-trityl-1H-imidazole (XI) can be accomplished using
a base such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3,
NaHCO.sub.3, aqueous NaOH, KOH, LiOH, NaH, NaOCH.sub.3,
NaOCH.sub.2CH.sub.3 or triethylamine in a solvent such as acetone,
DMF, DMSO, acetonitrile, toluene, EtOH, and MeOH and optionally if
appropriate a phase transfer catalyst such as tetrabutylammonium
bromide or an additive such as a crown ether, tetrabutylammonium
iodide or potassium iodide at room temperature 120.degree. C. for
1-24 hours.
[0098] Preferred conditions are K.sub.2CO.sub.3 in DMF at
80.degree. C. for 5 hours.
[0099] Step B: The cleavage of the trityl group can be effected
with a mineral acid such as HCl, H.sub.2SO.sub.4 or H.sub.3PO.sub.4
or a organic acid such as CF.sub.3COOH, CHCl.sub.2COOH, HOAc or
p-toluonesulfonic acid in a solvent such as CH.sub.2Cl.sub.2,
CHCl.sub.3, THF, MeOH, EtOH or H.sub.2O at 0 to 60.degree. C.
Preferred conditions are 2N HCl in EtOH at reflux for 1-3
hours.
Procedure D
Synthesis of C--C-linked 2-methyl-4-imidazoles
##STR00033##
[0101] An appropriate olefin such as aryl-1-butene (XII) can be
reacted at lower temperature with a nitrile such as acetonitrile
and nitrosonium fluoroborate to form an imidazole-N-oxide according
to Scheinbaum et al. (Tetrahedron Lett. 1971, p. 2205). To form the
imidazole derivative 1-4 the hydroxyfunction can be removed by
various reducing agents such as Red-Al, Titanium(III)-salts,
Lithiumaluminiumhydride or others as described by Lipshutz et al.
in Tetrahedron Lett. 25, 1984, p. 1319.
Procedure E
Synthesis of C--C-linked 2-amino-4-imidazoles
##STR00034##
[0103] An alpha-bromoketone of formula XIII is reacted with an
protected guanidine such as acetylguanidine (XIV) in a solvent such
as dimethylformamide followed by deprotection of the amino group to
form 2-aminoimidazole 1-5. This deprotection can be achieved for
instance by acid or base catalysed hydrolysis. In the case where
the protecting group is an acetyl group, deprotection is preferably
achieved by treatment with hydrochloric acid in a polar solvent
such as water, alkohols or mixtures of water and alkohols.
Procedure F
Synthesis of C--S-Linked Compounds
##STR00035## ##STR00036##
[0105] Step A: The alkylation of a substituted phenol (X) with
4-chloromethyl-1-trityl-1H-imidazole (XI) can be accomplished using
a base such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3,
NaHCO.sub.3, aqueous NaOH, KOH, LiOH, NaH, NaOCH.sub.3,
NaOCH.sub.2CH.sub.3 or triethylamine in a solvent such as acetone,
DMF, DMSO, acetonitrile, toluene, EtOH or MeOH and optionally if
appropriate a phase transfer catalyst such as tetrabutylammonium
bromide or an additive such as a crown ether, tetrabutylammonium
iodide or potassium iodide at room temperature to 120.degree. C.
for 1-24 hours.
[0106] Preferred conditions are K.sub.2CO.sub.3 in DMF at
80.degree. C. for 5 hrs.
[0107] Step B: The cleavage of the trityl group can be effected
with a mineral acid such as HCl, H.sub.2SO.sub.4 or H.sub.3PO.sub.4
or a organic acid such as CF.sub.3COOH, CHCl.sub.2COOH, HOAc or
p-toluonesulfonic acid in a solvent such as CH.sub.2Cl.sub.2,
CHCl.sub.3, THF, MeOH, EtOH or H.sub.2O at 0 to 60.degree. C.
Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs.
[0108] Step C: The oxidation of the thioether (II-4) to the
corresponding sulfoxide (II-5) can be accomplished by oxidants such
as mCPBA, isopropyl 2-iodoxybenzoate, oxone or natriumperiodate in
a solvent such as CH.sub.2Cl.sub.2, dichloroethane, toluene,
acetonitrile, MeOH at temperatures from 0.degree. C. to reflux.
[0109] Preferred conditions are 1 equivalent of mCPBA in
CH.sub.2Cl.sub.2 at 0.degree. C. to room temperature for 1-5
hours.
[0110] Step D: The oxidation of the thioether (II-4) to the
corresponding sulfoxide (II-6) can be accomplished by oxidants such
as mCPBA, H.sub.2O.sub.2, oxone or sodium wolframate in a solvent
such as CH.sub.2Cl.sub.2, dichloroethane, toluene, acetonitrile,
THF, acetone, or MeOH at temperatures from 0.degree. C. to
reflux.
[0111] Preferred conditions are 2 equivalent of mCPBA in
CH.sub.2Cl.sub.2 at 0.degree. C. to room temperature for 1 to 5
hrs.
Procedure E
Synthesis of C--N-Linked Compounds
##STR00037##
[0113] Step A: The coupling of a substituted arylcarboxylic acid
(XVI) with a suitably protected 4-amino-imidazole compound (XVII)
to afford an amide compound (IXX) can be accomplished using a
coupling agent such as
2-(1h-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU) or
2-(1h-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU) or
o-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium
hexafluorophosphate (HATU) and a base such as triethylamine or
ethyldiisopropylamine in a solvent such as THF, DMF, or
dichloromethane. Suitable nitrogen protecting groups include
tert-butoxycarbamate (BOC), trityl, dimethylaminosulfonyl and
trimethylsilyl-ethyl (SEM). Preferred conditions are TBTU and
ethyldiisopropylamine in DMF at 40.degree. C. for 16 hrs, and a
preferred protecting group is trityl.
[0114] Step B: The coupling of a substituted arylcarboxylic acid
chloride (XVIII) with a suitably protected 4-amino-imidazole
compound (XVII) to afford an amide compound (IXX) can be
accomplished using a base such as pyridine, triethylamine or
ethyldiisopropylamine in a solvent such as THF, DMF or
dichloromethane and optionally using a catalyst such as
N,N-dimethylformamide or 4-N,N-dimethylaminopyridine (DMAP)
[0115] Preferred conditions are triethylamine in dichloromethane at
room temperature for 1 hour, and a preferred protecting group is
trityl.
[0116] Step C: The reduction of an amide (IXX) to an amine (II-7)
can be accomplished using a metal hydride reducing agent such as
lithium aluminium hydride or a borane reagent such as
borane-tetrahydrofuran complex in a solvent such as dioxane, ether
or tetrahydrofuran at elevated temperature.
[0117] Preferred conditions are lithium aluminium hydride in
tetrahydrofuran at reflux temperature for 16 hours.
[0118] Step D: The deprotection conditions depend on the nature of
the protecting group employed and many methods are well known in
the art.
[0119] In the case of the trityl protecting group, preferred
deprotection conditions are 4 M aqueous hydrochloric acid in
dioxane at room temperature for 1-2 hours.
Isolation and Purification of the Compounds
[0120] Isolation and purification of the compounds and
intermediates described herein can be effected, if desired, by any
suitable separation or purification procedure such as, for example,
filtration, extraction, crystallization, column chromatography,
thin-layer chromatography, thick-layer chromatography, preparative
low or high-pressure liquid chromatography or a combination of
these procedures. Specific illustrations of suitable separation and
isolation procedures can be had by reference to the preparations
and examples herein below. However, other equivalent separation or
isolation procedures could, of course, also be used. Racemic
mixtures of chiral compounds of formula I can be separated using
chiral HPLC.
Salts of Compounds of Formula I
[0121] The compounds of formula I are basic and may be converted to
a corresponding acid-addition salt. The conversion is accomplished
by treatment with at least a stoichiometric amount of an
appropriate acid, such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as acetic acid, propionic acid, glycolic acid,
pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,
maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the
like. Typically, the free base is dissolved in an inert organic
solvent such as diethyl ether, ethyl acetate, chloroform, ethanol
or methanol and the like, and the acid added in a similar solvent.
The temperature is maintained between 0.degree. C. and 50.degree.
C. The resulting salt precipitates spontaneously or may be brought
out of solution with a less polar solvent.
[0122] The acid-addition salts of the basic compounds of formula I
may be converted to the corresponding free bases by treatment with
at least a stoichiometric equivalent of a suitable base such as
sodium or potassium hydroxide, potassium carbonate, sodium
bicarbonate, ammonia, and the like.
[0123] Another aspect of the present invention is a pharmaceutical
composition comprising a compound of formula I, or a
pharmaceutically-suitable acid-addition salt thereof, and a
therapeutically-inert carrier. Processes for the production of such
a composition are also aspects of the present invention. Such a
process comprises bringing one or more compounds of formula I
and/or a pharmaceutically-suitable salt(s) thereof and, if desired,
one or more other therapeutically-valuable substances into a
galenical administration form together with one or more
therapeutically-inert carriers.
[0124] The term "therapeutically-inert carrier" means that the
carrier is not toxic and does not interfere with the ability of the
active compound(s) to elicit the biological or medical response of
a tissue system, animal or human that is being sought by the
researcher, veterinarian, medical doctor or other clinician. The
therapeutically-inert carrier for use in the composition of the
present invention may be inorganic or organic. Lactose, corn starch
or derivatives thereof, talc, stearic acids or its salts and the
like can be used, for example, as such carriers for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carriers for
soft gelatine capsules are, for example, vegetable oils, waxes,
fats, semi-solid and liquid polyols and the like. Depending on the
nature of the active substance no carriers are however usually
required in the case of soft gelatine capsules. Suitable carriers
for the production of solutions and syrups are, for example, water,
polyols, glycerol, vegetable oil and the like. Suitable carriers
for suppositories are, for example, natural or hardened oils,
waxes, fats, semi-liquid or liquid polyols and the like.
[0125] The pharmaceutical composition can, moreover, contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. The
composition can also contain still other therapeutically valuable
substances.
[0126] The pharmaceutical composition of the present invention can
be administered orally, e.g. in the form of tablets, coated
tablets, dragees, hard and soft gelatine capsules, solutions,
emulsions or suspensions. The administration can, however, also be
effected rectally, e.g. in the form of suppositories, and
parenterally, e.g. in the form of injection solutions.
[0127] The present invention relates also to a method for treating
or preventing a disease or disorder in a patient comprising
administering a therapeutically-effective amount of a compound of
the present invention to a patient. A "therapeutically-effective
amount" is the amount of the subject compound that will elicit the
biological or medical response of a tissue system, animal or human
that is being sought by the researcher, veterinarian, medical
doctor or other clinician. The above method may involve the
administration of a composition which comprises a
therapeutically-effective amount of the compound such as the
composition described above.
[0128] The therapeutically-effective amount can vary within wide
limits and will, of course, have to be adjusted to the individual
requirements in each particular case. In the case of oral
administration the dosage for adults can vary from about 0.01 mg to
about 1000 mg per day of a compound of general formula I or of the
corresponding amount of a pharmaceutically-suitable salt thereof.
The daily dosage may be administered as single dose or in divided
doses and, in addition, the upper limit can also be exceeded when
this is found to be indicated.
EXAMPLES
[0129] The following examples illustrate the invention but are not
intended to limit its scope.
Example 1
4-(2-Phenyl-butyl)-1H-imidazole
a) 4-(2-Phenyl-but-1-enyl)-1-trityl-1H-imidazole
##STR00038##
[0131] To a stirred solution of
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(1.24 g; CAS 473659-21-1) at room temperature (r.t.) in THF (20 ml)
under an argon atmosphere was added potassium tert-butylate (301
mg). After 15 minutes stirring at room temperature, propiophenone
(0.3 ml) was added in one portion. The mixture was heated to
80.degree. C. and stirring at that temperature was continued for 2
days. The compact suspension was cooled to r.t. and the solid was
filtered off and washed with THF. The filtrate was concentrated to
leave a dark violet viscous oil. This was taken up in ethyl acetate
(EtOAc) and washed with brine. The aqueous phase was back extracted
with EtOAc. The combined organics were washed with brine, dried
over MgSO.sub.4, filtered and concentrated. The crude product was
purified by column chromatography (silica gel; gradient
cyclohexane->cyclohexane/EtOAc 3:2) to give
4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (269 mg; not
completely pure) as an off-white solid. MS (ISP): 243.2
([Trt].sup.+)
b) 4-(2-Phenyl-butyl)-1H-imidazole
##STR00039##
[0133] To a stirred solution of
4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (260 mg) at r.t. in
methanol (5 ml) and dichloromethane (2 ml) under an argon
atmosphere was added 10% Pd/C (26 mg). The mixture was then stirred
at r.t. under a hydrogen atmosphere for 17 hours. The catalyst was
filtered off and washed with methanol. The filtrate was
concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 9:1 to give
4-(2-phenyl-butyl)-1H-imidazole (18 mg) as colorless gum. MS (ISP):
201.3 ([M+H].sup.+)
Example 2
4-(3-Methyl-2-phenyl-butyl)-1H-imidazole
a) 4-(3-Methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole
##STR00040##
[0135] To a stirred suspension of
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(921 mg; CAS 473659-21-1) at r.t. in THF (20 ml) under an argon
atmosphere was added potassium tert-butylate (241 mg). The mixture
was then stirred at r.t. for 15 minutes, and isobutyrophenone (0.25
ml) was added in one portion. The mixture (clear brown orange
solution) was heated to 80.degree. C. for 21 hours. The reaction
mixture was filtered and the cake was washed with EtOAc. The
filtrate was concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
cyclohexane->cyclohexane/EtOAc 1:1) to give
4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (91 mg; not
completely pure) as orange sticky solid. MS (ISP): 243.2
([Trt].sup.+)
b) 4-(3-Methyl-2-phenyl-butyl)-1-trityl-1H-imidazole
##STR00041##
[0137] To a stirred solution of
4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (87 mg) at
r.t. in methanol (4 ml) and CH.sub.2Cl.sub.2 (1 ml) under an argon
atmosphere was added the 10% Pd/C (10 mg). The mixture was then
stirred at r.t. under a hydrogen atmosphere for 38 hours. The
catalyst was filtered off and washed with MeOH. The filtrate was
concentrated to leave
4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (82 mg) of an
off-white sticky solid which was used in the next step without
further purification. MS (ISP): 243.2 ([Trt].sup.+)
c) 4-(3-Methyl-2-phenyl-butyl)-1H-imidazole
##STR00042##
[0139] To a stirred suspension of
4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (80 mg) at r.t.
in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3
ml). The mixture (suspension) was heated to reflux (turning to a
clear light yellow solution when reaching 90.degree. C.) and
stirred for 2 hours and 30 minutes, then cooled to r.t. and
concentrated to leave a light brown sticky solid. This was taken up
in H.sub.2O and basified to pH>12 by the addition of 4 N NaOH.
The product was extracted with CH.sub.2Cl.sub.2/MeOH 9:1. The
combined organics were dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 85:15) to give
4-(3-methyl-2-phenyl-butyl)-1H-imidazole (8 mg) as colorless gum.
MS (ISP): 215.4 ([M+H].sup.+)
Example 3
4-(3,3-Dimethyl-2-phenyl-butyl)-1H-imidazole
a) 4-(3,3-Dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole
##STR00043##
[0141] To a stirred suspension of
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(341 mg; CAS 473659-21-1) at r.t. in THF (7.5 ml) under an argon
atmosphere was added potassium tert-butylate (83 mg). The mixture
was then stirred at r.t. for 15 minutes, and
2,2-dimethylpropiophenone (0.1 ml) was added in one portion. The
mixture (clear brown orange solution) was heated to 80.degree. C.
and stirring at that temperature was continued for 24 hours. The
reaction mixture was directly adsorbed on silica gel. The product
was isolated by chromatography (gradient:
cyclohexane->cyclohexane/EtOAc 65:35) to give
4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (135 mg;
not completely pure) as light yellow solid. MS (ISP): 243.2
([Trt].sup.+)
b) 4-(3,3-Dimethyl-2-phenyl-butyl)-1H-imidazole
##STR00044##
[0143] To a stirred solution of
4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (121 mg)
at r.t. in methanol (5 ml) and dichloromethane (1 ml) under an
argon atmosphere was added 10% Pd/C (12 mg). The mixture was
stirred under a hydrogen atmosphere (balloon) for 17 hours. The
catalyst was filtered off and washed with methanol. The filtrate
was concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 9:1) to give
4-(3,3-dimethyl-2-phenyl-butyl)-1H-imidazole (25 mg) as colorless
gum. MS (ISP): 229.4 ([M+H].sup.+)
Example 4
4-(1-Methoxy-2-phenyl-ethyl)-1H-imidazole
a) 2-(tert-Butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic
acid dimethylamide
##STR00045##
[0145] To a stirred, cooled (-78.degree. C.) solution of
2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid
dimethylamide (1.02 g; CAS 129378-52-5) in THF (20 ml) under an
argon atmosphere was added dropwise butyl lithium (3.3 ml; 1.6 M
solution in hexanes) over a period of 10 minutes. After 30 minutes
of stirring, DMF (1.3 ml) was added over a period of 5 minutes and
the mixture (clear light yellow solution) was stirred at
-78.degree. C. for another 2 hours. The mixture was quenched with
saturated aqueous NH.sub.4Cl and diluted with EtOAc. The aqueous
phase was back extracted with EtOAc. The combined organics were
washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and
concentrated to give
2-(tert-butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic acid
dimethylamide (1.22 g) as viscous orange oil which was used in the
next reaction step without further purification. MS (ISP): 318.3
([M+H].sup.+)
b)
2-(tert-Butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole--
1-sulfonic acid dimethylamide
##STR00046##
[0147] Benzyl bromide (4.1 ml) was added dropwise to a stirred
suspension of magnesium (1.01 g) in diethyl ether (10 ml). When the
vigorously exothermic reaction was complete, the supernatant
solution was decanted from the solid and kept in the fridge, ready
for use. An aliquot of this solution (1 ml) was added dropwise
(exothermic!) to a cooled (0.degree. C., ice bath) stirred solution
of 2-(tert-butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic
acid dimethylamide (725 mg) at r.t. in THF (5 ml) under an argon
atmosphere. When addition was complete, stirring at r.t. was
continued overnight. The mixture was quenched by the addition of
saturated aqueous NH.sub.4Cl and extracted with EtOAc. The aqueous
phase was back extracted with EtOAc. The combined organics were
washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
cyclohexane->cyclohexane/EtOAc 25:75) to give
2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1--
sulfonic acid dimethylamide (168 mg) as light yellow solid. MS
(ISP): 410.1 ([M+H].sup.+)
c)
2-(tert-Butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole--
1-sulfonic acid dimethylamide
##STR00047##
[0149] To a stirred solution of
2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1--
sulfonic acid dimethylamide (160 mg) at r.t. in THF (5 ml) under an
argon atmosphere was added NaH (18 mg; 55% dispersion in mineral
oil) in one portion. After 1 hour stirring at r.t., MeI (0.04 ml)
was added and stirring at r.t. was continued overnight. The mixture
was diluted with EtOAc and washed with H.sub.2O. The aqueous phase
was back extracted with EtOAc. The combined organics were washed
with H.sub.2O and brine, dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
cyclohexane->cyclohexane/EtOAc 65:35) to give
2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1--
sulfonic acid dimethylamide (111 mg) as light yellow viscous oil.
MS (ISP): 424.3 ([M+H].sup.+)
d) 4-(1-Methoxy-2-phenyl-ethyl)-1H-imidazole
##STR00048##
[0151] To a stirred suspension of
2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1--
sulfonic acid dimethylamide (105 mg) at r.t. in ethanol (3 ml)
under an argon atmosphere was added 2 N HCl (3 ml). The mixture was
heated to reflux for 3 hours. The mixture was cooled to r.t. and
concentrated to leave a light yellow solid which was taken up in
H2O and brought to pH 12 by the addition of 4 N NaOH. The product
was extracted with CH.sub.2Cl.sub.2/MeOH 4:1. The combined organics
were dried over MgSO.sub.4, filtered and concentrated. The crude
product was purified by column chromatography (silica gel;
gradient: CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 9:1) to give
4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole (38 mg) as white solid.
MS (ISP): 203.4 ([M+H].sup.+)
Example 5
4-[2-(2-Chloro-phenyl)-ethyl]-1H-imidazole
a) 4-[2-(2-Chloro-phenyl)-vinyl]-1-trityl-1H-imidazole
##STR00049##
[0153] To a stirred suspension of
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(448 mg; CAS 473659-21-1) at r.t. in THF (7 ml) under an argon
atmosphere were added potassium tert-butylate (109 mg) and
2-chlorobenzaldehyde (114 mg). The mixture (clear brown orange
solution) was heated to 80.degree. C. over night. The reaction
mixture was cooled to r.t and concentrated. The crude product was
purified by column chromatography (silica gel; gradient:
cyclohexane->cyclohexane/EtOAc 3:2) to give
4-[2-(2-chloro-phenyl)-vinyl]-1-trityl-1H-imidazole (329 mg) as
off-white solid. MS (ISP): 243.3 ([Trt].sup.+)
b) 4-[2-(2-Chloro-phenyl)-ethyl]-1H-imidazole
##STR00050##
[0155] To a stirred mixture of
4-[2-(2-chloro-phenyl)-vinyl]-1-trityl-1H-imidazole (329 mg) at
r.t. in ethanol (7 ml) and chloroform (3 ml) under an argon
atmosphere were added acetic acid (0.2 ml) and 10% Pd/C (30 mg).
The mixture was hydrogenated (ambient pressure) over night. The
catalyst was filtered off and washed with ethanol. The mixture was
concentrated to leave a light brown gum. This material was taken up
in ethanol (3 ml) and 2 N HCl (3 ml) and heated to reflux for 3 h.
Then, the mixture was cooled to r.t., concentrated. The residual
solid was taken up in 1 N NaOH (10 ml) and extracted with
CH.sub.2Cl.sub.2/MeOH 4:1. The combined organics were dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by column chromatography (silica gel; gradient:
CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 9:1) to give
4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole (44 mg) as light brown
gum. MS (ISP): 207.1 ([M+H].sup.+)
Example 6
4-[2-(2-Ethyl-phenyl)-ethyl]-1H-imidazole
##STR00051##
[0157] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 2-ethylbenzaldehyde and then
converted to 4-[2-(2-ethyl-phenyl)-ethyl]-1H-imidazole, as a
colorless viscous oil. MS (ISP): 201.3 ([M+H].sup.+)
Example 7
4-[2-(2-Trifluoromethyl-phenyl)-ethyl]-1H-imidazole
##STR00052##
[0159] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 2-(trifluormethyl)benzaldehyde
and then converted to
4-[2-(2-trifluoromethyl-phenyl)-ethyl]-1H-imidazole, as a colorless
viscous oil. MS (ISP): 241.3 ([M+H].sup.+)
Example 8
4-[2-(2-Methoxy-phenyl)-ethyl]-1H-imidazole
##STR00053##
[0161] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 2-methoxybenzaldehyde and then
converted to 4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole, as a
colorless viscous oil. MS (ISP): 203.1 ([M+H].sup.+)
Example 9
{2-[2-(1H-Imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine
##STR00054##
[0163] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with
2-(N,N-dimethylamino)benzaldehyde and then converted to
{2-[2-(1H-Imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine, as a light
yellow viscous oil. MS (ISP): 216.3 ([M+H].sup.+)
Example 10
4-{2-[2-(1H-Imidazol-4-yl)-ethyl]-phenyl}-morpholine
##STR00055##
[0165] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 2-morpholinobenzaldehyde and
then converted to
4-{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-morpholine, as a light
yellow viscous oil. MS (ISP): 258.3 ([M+H].sup.+)
Example 11
4-[2-(3-Chloro-phenyl)-ethyl]-1H-imidazole
##STR00056##
[0167] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 3-chlorobenzaldehyde and then
converted to 4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole, as an
off-white solid. MS (ISP): 207.1 ([M+H].sup.+)
Example 12
4-[2-(3-Fluoro-phenyl)-ethyl]-1H-imidazole
##STR00057##
[0169] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 3-fluorobenzaldehyde and then
converted to 4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole, as an
off-white solid. MS (ISP): 191.1 ([M+H].sup.+)
Example 13
4-[2-(3-Trifluoromethyl-phenyl)-ethyl]-1H-imidazole
##STR00058##
[0171] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 3-(trifluoromethyl)benzaldehyde
and then converted to
4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole, as an
off-white viscous oil. MS (ISP): 241.1 ([M+H].sup.+)
Example 14
4-[2-(3-Methoxy-phenyl)-ethyl]-1H-imidazole
##STR00059##
[0173] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 3-methoxybenzaldehyde and then
converted to 4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole, as an
off-white solid. MS (ISP): 203.3 ([M+H].sup.+)
Example 15
4-[2-(3-Trifluoromethoxy-phenyl)-ethyl]-1H-imidazole
##STR00060##
[0175] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 3-(trifluoromethoxy)benzaldehyde
and then converted to
4-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-imidazole, as a light
yellow viscous oil. MS (ISP): 257.3 ([M+H].sup.+)
Example 16
4-[2-(4-Chloro-phenyl)-ethyl]-1H-imidazole
##STR00061##
[0177] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 4-chlorobenzaldehyde and then
converted to 4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole, as an
off-white solid. MS (ISP): 207.1 ([M+H].sup.+)
Example 17
4-[2-(3,5-Dichloro-phenyl)-ethyl]-1H-imidazole
##STR00062##
[0179] In analogy to example 5,
(1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester
(CAS 473659-21-1) was reacted with 3,5-dichlorobenzaldehyde and
then converted to 4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole,
as an off-white solid. MS (ISP): 241.1 ([M+H].sup.+)
Example 18
2-Methyl-5-phenethyl-1H-imidazole
a) 2-Methyl-5-phenethyl-imidazol-1-ol
##STR00063##
[0181] To a solution of nitrosonium tetrafluoroborate (0.564 g,
4.83 mmol) in acetonitrile (8 ml) 4-phenyl-1-butene was added at
-30.degree. C. The mixture was stirred for 1 hour at this
temperature, then 0.5 ml of water was added carefully. At room
temperature saturated ammonium chloride solution was added and the
acetonitrile was evaporated in vacuo. The pH of the remaining
aqueous solution was adjusted to neutral with a small amount of
sodium hydroxide and extracted with dichloromethane. The organic
layer was separated, dried over magnesium sulfate and evaporated.
The residue was purified using flash chromatography (SiO.sub.2,
dichloromethane/methanol=9:1) to yield an off-white solid (0.245 g,
17%); MS (ISP): 202.9 ([M+H].sup.+)
b) 2-Methyl-5-phenethyl-1H-imidazole
##STR00064##
[0183] To a solution of 2-methyl-5-phenethyl-imidazol-1-ol (0.20 g,
1.0 mmol) in methanol (3.5 ml) titanium(III)-chloride solution (2.5
ml, 15%) was added and the mixture was stirred overnight at room
temperature. First saturated sodium bicarbonate solution then
diluted sodium hydroxide solution was added to achieve a basic pH.
The mixture was extracted twice with dichloromethane, the combined
organic layers were dried over magnesium sulfate and evaporated.
The residue was purified by column chromatography
(dichloromethane/methanol=9:1) to yield a white solid (0.14 mg,
75%); MS (EI): 186.1 (M.sup.+.).
Example 19
5-Phenethyl-1H-imidazol-2-ylamine
##STR00065##
[0185] To a solution of 1-acetylguanidine (1.34 g, 13.2 mmol) in
dimethylformamide (7 ml) a solution of 1-bromo-4-phenyl-butan-2-one
(1.5 g, 6.6 mmol) in dimethylformamide (7 ml) was added at
0.degree. C. The mixture was stirred overnight at room temperature
and then the solvent was evaporated. Upon addition of ethyl
acetate/heptane (1:1) a white solid was formed that was filtered
off and washed with ethyl acetate/heptane (1:1). After drying in
vacuo the solid was dissolved in a mixture of concentrated
hydrochloric acid (2 ml) and methanol (4 ml) and stirred for 2.5
hours at 85.degree. C. The solvent was evaporated and the residue
was purified by chromatography (column: Isolute.RTM. Flash-NH.sub.2
from Separtis; eluent: ethyl acetate/methanol=1:1) to yield a light
yellow solid (0.063 mg, 5%); MS (EI): 187.2 (M.sup.+.).
Example 20
4-(2,3-Dichloro-phenoxymethyl)-1H-imidazole
a) 4-(2,3-Dichloro-phenoxymethyl)-1-trityl-1H-imidazole
##STR00066##
[0187] To a stirred solution of
4-chloromethyl-1-trityl-1H-imidazole (400 mg; CAS 103057-10-9) at
r.t. in DMF (5 ml) under an argon atmosphere were added
2,3-dichlorophenol (273 mg) and K.sub.2CO.sub.3 (385 mg). The
reaction mixture was heated to 80.degree. C. for 5 hours, then
cooled to r.t., diluted with EtOAc and washed with 1 N NaOH. The
aqueous phase was back extracted with EtOAc. The combined organics
were washed with H.sub.2O and brine, dried over MgSO.sub.4,
filtered and concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
cyclohexane->cyclohexane/EtOAc 1:1) to give
4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (360 mg) as
white solid. MS (ISP): 243.3 ([Trt].sup.+)
b) 4-(2,3-Dichloro-phenoxymethyl)-1H-imidazole
##STR00067##
[0189] To a stirred suspension of
4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (150 mg) at
r.t. in ethanol (2 ml) under an argon atmosphere was added 2 N HCl
(3 ml). The mixture was heated to reflux for 6 hours, then
concentrated to leave an off-white solid. This was taken up in
saturated aqueous Na.sub.2CO.sub.3 and extracted with
CH.sub.2Cl.sub.2/MeOH 4:1. The combined organics were dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by column chromatography (silica gel; gradient:
CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 4:1) to give
4-(2,3-dichloro-phenoxymethyl)-1H-imidazole (65 mg) as white solid.
MS (ISP): 243.4 ([M+H].sup.+)
Example 21
4-(2-Ethyl-phenoxymethyl)-1H-imidazole
##STR00068##
[0191] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-ethylphenol and then converted to
4-(2-ethyl-phenoxymethyl)-1H-imidazole, as awaxy off-white solid.
MS (ISP): 203.1 ([M+H].sup.+)
Example 22
4-(2-Isopropyl-phenoxymethyl)-1H-imidazole
##STR00069##
[0193] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-isopropylphenol and then converted to
4-(2-isopropyl-phenoxymethyl)-1H-imidazole, as a waxy off-white
solid. MS (ISP): 217.4 ([M+H].sup.+)
Example 23
4-(2-Trifluoromethyl-phenoxymethyl)-1H-imidazole
##STR00070##
[0195] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-trifluoromethylphenol and then converted to
4-(2-trifluoromethyl-phenoxymethyl)-1H-imidazole, as a white solid.
MS (ISP): 243.4 ([M+H].sup.+)
Example 24
4-(2-Benzyl-phenoxymethyl)-1H-imidazole
##STR00071##
[0197] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-benzylphenol and then converted to
4-(2-benzyl-phenoxymethyl)-1H-imidazole, as a waxy white solid. MS
(ISP): 265.1 ([M+H].sup.+)
Example 25
4-(2-Methoxy-phenoxymethyl)-1H-imidazole
##STR00072##
[0199] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-methoxyphenol and then converted to
4-(2-methoxy-phenoxymethyl)-1H-imidazole as an off-white amorphous
solid. MS (ISP): 205.1 ([M+H].sup.+)
Example 26
4-(2-Isopropoxy-phenoxymethyl)-1H-imidazole
##STR00073##
[0201] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-isopropoxyphenol and then converted to
4-(2-isopropoxy-phenoxymethyl)-1H-imidazole as an off-white solid.
MS (ISP): 233.3 ([M+H].sup.+)
Example 27
4-(2-Trifluoromethoxy-phenoxymethyl)-1H-imidazole
##STR00074##
[0203] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-trifluoromethoxyphenol and then converted to
4-(2-trifluoromethoxy-phenoxymethyl)-1H-imidazole as an off-white
solid. MS (ISP): 259.1 ([M+H].sup.+)
Example 28
4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole
a) 4-(2-Benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole
##STR00075##
[0205] In analogy to example 20.a.,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2-benzyloxyphenol to give
4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole as a yellow
viscous oil. MS (ISP): 523.5 ([M+H].sup.+)
b) 4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole
##STR00076##
[0207] A solution of
4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole (34 mg) in MeOH
(2 ml) was treated with AcOH (0.1 ml) and was heated to 70.degree.
C. for 5 hours. The mixture was concentrated. The crude product was
purified by column chromatography to give
4-(2-benzyloxy-phenoxymethyl)-1H-imidazole (11 mg) as a colorless
amorphous solid. MS (ISP): 281.4 ([M+H].sup.+)
Example 29
2-(1H-Imidazol-4-ylmethoxy)-phenol
##STR00077##
[0209] Under conditions as described in example 20.b,
4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole (example 28.a)
was converted to 2-(1H-Imidazol-4-ylmethoxy)-phenol as an off-white
solid. MS (ISP): 191.4 ([M+H].sup.+)
Example 30
4-(3-Trifluoromethyl-phenoxymethyl)-1H-imidazole
##STR00078##
[0211] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3-trifluoromethylphenol and then converted to
4-(3-trifluoromethyl-phenoxymethyl)-1H-imidazole as a white solid.
MS (ISP): 243.3 ([M+H].sup.+)
Example 31
4-(3-Trifluoromethoxy-phenoxymethyl)-1H-imidazole
##STR00079##
[0213] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3-trifluoromethoxyphenol and then converted to
4-(3-trifluoromethoxy-phenoxymethyl)-1H-imidazole as a colorless
oil. MS (ISP): 259.0 ([M+H].sup.+)
Example 32
[3-(1H-Imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine
##STR00080##
[0215] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3-dimethylaminophenol and then converted to
[3-(1H-imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine as an off-white
solid. MS (ISP): 218.4 ([M+H].sup.+)
Example 33
4-[-(1H-Imidazol-4-ylmethoxy)-phenyl]-morpholine
##STR00081##
[0217] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3-morpholinophenol and converted to
4-[3-(1H-imdazol-4-ylmethoxy)-phenyl]-morpholine as a white solid.
MS (ISP): 260.3 ([M+H].sup.+)
Example 34
4-(2,6-Diethyl-phenoxymethyl)-1H-imidazole
##STR00082##
[0219] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2,6-diethylphenol and converted to
4-(2,6-diethyl-phenoxymethyl)-1H-imidazole as a colorless oil. MS
(ISP): 231.4 ([M+H].sup.+)
Example 35
4-(2,3-Difluoro-phenoxymethyl)-1H-imidazole
##STR00083##
[0221] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 2,3-difluorophenol and converted to
4-(2,3-difluoro-phenoxymethyl)-1H-imidazole as a white solid. MS
(ISP): 211.1 ([M+H].sup.+)
Example 36
4-(3,4-Dichloro-phenoxymethyl)-1H-imidazole
##STR00084##
[0223] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3,4-dichlorophenol and converted to
4-(3,4-dichloro-phenoxymethyl)-1H-imidazole as a white solid. MS
(ISP): 243.1 ([M+H].sup.+)
Example 37
4-(4-Chloro-3-fluoro-phenoxymethyl)-1H-imidazole
##STR00085##
[0225] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 4-chloro-3-fluorophenol and converted to
4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole as a white solid.
MS (ISP): 227.1 ([M+H].sup.+)
Example 38
4-(3,4-Difluoro-phenoxymethyl)-1H-imidazole
##STR00086##
[0227] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3,4-difluorophenol and converted to
4-(3,4-difluoro-phenoxymethyl)-1H-imidazole as a white solid. MS
(ISP): 211.1 ([M+H].sup.+)
Example 39
5-(Benzofuran-6-yloxymethyl)-1H-imidazole
##STR00087##
[0229] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 6-hydroxybenzofurane and converted to
5-(benzofuran-6-yloxymethyl)-1H-imidazole.
Example 40
4-(3-Chloro-5-fluoro-phenoxymethyl)-1H-imidazole
##STR00088##
[0231] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 3-chloro-5-fluorophenol and converted to
4-(3-chloro-5-fluoro-phenoxymethyl)-1H-imidazole as an off-white
amorphous solid. MS (ISP): 227.1 ([M+H].sup.+)
Example 41
5-(4-Bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole
##STR00089##
[0233] In analogy to example 20,
4-chloromethyl-1-trityl-1H-imidazole (CAS 103057-10-9) was reacted
with 4-bromo-2,6-dimethylphenol and converted to
5-(4-bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole.
Example 42
5-(2,3-Dichloro-phenylsulfanylmethyl)-1-imidazole
a) 5-(2,3-Dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole
##STR00090##
[0235] A solution of 4-chloromethyl-1-trityl-1H-imidazole (600 mgl;
CAS 103057-10-9) in DMF (12 ml) was treated under an Argon
atmosphere with potassium carbonate (578 mg) and
2,3-dichlorobenzenethiol (449 mg). The reaction mixture was heated
to 80.degree. C. for 5 hours, then cooled to r.t., taken up in
water and extracted with EtOAc. The organic layer was washed with
water, dried over MgSO4 and concentrated. The crude product was
purified by column chromatography (silica gel; gradient:
cyclohexane->cyclohexane/EtOAc 1:1) to give
5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole (564 mg)
as an off-white solid. MS (ISP): 243.3 ([Trt].sup.+)
b) 5-(2,3-Dichloro-phenylsulfanylmethyl)-1-imidazole
##STR00091##
[0237] In analogy to example 20.b,
5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole was
converted to 5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole as
an off-white solid. MS (ISP): 259.0 ([M+H].sup.+)
Example 43
5-(2,3-Dichloro-benzenesulfinylmethyl)-1-imidazole
a) 5-(2,3-Dichloro-benzenesulfinylmethyl)-1-trityl-1-imidazole
##STR00092##
[0239] A solution of
5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole (250 mg;
example 42.a) in CH.sub.2Cl.sub.2 (20 ml) was cooled under an Argon
atmosphere to 0.degree. and treated with meta-chloroperbenzoic acid
(86 mg). The reaction mixture was stirred for 3 hours at 0.degree.
C., then concentrated. The crude product was purified by column
chromatography (silica gel; gradient:
CH.sub.2Cl.sub.2->CH.sub.2Cl.sub.2/MeOH 98:2) to give
5-(2,3-dichloro-benzenesulfinylmethyl)-1-trityl-1-imidazole (121
mg) as a white solid. MS (ISP): 517.3 ([M+H].sup.+)
b) 5-(2,3-Dichloro-benzenesulfinylmethyl)-1-imidazole
##STR00093##
[0241] In analogy to example 20.b,
5-(2,3-dichloro-benzenesulfinylmethyl)-1-trityl-1-imidazole was
converted to 5-(2,3-dichloro-benzenesulfinylmethyl)-1-imidazole as
a white solid. MS (ISP): 275.1 ([M+H].sup.+)
Example 44
5-(2,3-Dichloro-benzenesulfonylmethyl)-1H-imidazole
##STR00094##
[0243] In analogy to example 43, but using 2 equivalents of
meta-chloroperbenzoic acid in the first reaction step,
5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole (250 mg;
example 42.a) was converted to
5-(2,3-dichloro-benzenesulfonylmethyl)-1H-imidazole as a white
solid. MS (ISP): 291.0 ([M+H].sup.+)
Example 45
4-Benzene sulfinylmethyl-5-methyl-1H-imidazole
##STR00095##
[0245] The title compound was prepared in analogy to example 43
using 4-chloromethyl-5-methyl-1-trityl-1H-imidazole (CAS
106147-85-7) for the alkylation of benzenethiol.
Example 46
4-(4-Chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole
##STR00096##
[0247] The title compound was prepared in analogy to example 42
using 4-chloromethyl-5-methyl-1-trityl-1H-imidazole (CAS
106147-85-7) for the alkylation of 4-chlorobenzenethiol.
Example 47
4-(Naphthalen-2-ylsulfanylmethyl)-1H-imidazole
##STR00097##
[0249] The title compound was prepared in analogy to example 42
starting from naphthalene-2-thiol.
Example 48
Benzyl-(1H-imidazol-4-yl)-amine hydrochloride
a) N-(1-Trityl-1H-imidazol-4-yl)-benzamide
##STR00098##
[0251] To a solution of 4-amino-1-tritylimidazole (0.30 g, 0.92
mmol) in dichloromethane (4 ml) were added sequentially
triethylamine (0.19 ml, 1.37 mmol) and benzoyl chloride (0.13 ml,
1.12 mmol). The reaction mixture was stirred at room temperature
for 30 minutes, then diluted with dichloromethane and washed
sequentially with water, saturated aq. NaHCO.sub.3 solution, water
and saturated brine. The organic layer was separated, dried over
sodium sulfate and concentrated in vacuo. The residue was purified
by chromatography on silica gel (eluant: methanol/dichloromethane
0:100 to 10:90) to yield the title compound as an orange solid
(0.36 g, 92%); MS (ISP): 430.3 ([M+H].sup.+).
b) Benzyl-(1-trityl-1H-imidazol-4-yl)-amine
##STR00099##
[0253] To a solution of N-(1-trityl-1H-imidazol-4-yl)-benzamide
(0.36 g, 0.83 mmol) in tetrahydrofuran (10 ml) was added
portionwise lithium aluminium hydride (0.16 g, 4.14 mmol). The
reaction mixture was stirred at 80.degree. C. for 16 hours, then
cooled to room temperature and water added dropwise. The mixture
was stirred at room temperature for 20 minutes and then extracted
with ethyl acetate. The organic layer was separated, washed with
water, dried over magnesium sulfate and concentrated in vacuo. The
residue was purified by chromatography on silica gel (eluant:
methanol/dichloromethane 0:100 to 10:90) to yield the title
compound as a white solid (0.15 g, 44%); MS (ISP): 416.5
([M+H].sup.+).
c) Benzyl-(1H-imidazol-4-yl)-amine hydrochloride
##STR00100##
[0255] Benzyl-(1-trityl-1H-imidazol-4-yl)-amine (0.15 g, 0.35 mmol)
was dissolved in a 4 M solution of HCl in dioxane (5 ml). The
mixture was stirred at room temperature for 90 minutes and then
concentrated in vacuo. The residue was triturated in ether to yield
the title compound as an off-white solid (73 mg, 100%); MS (ISP):
174.4 ([M+H].sup.+).
[0256] Compounds of examples 1-48 are new. Compounds of examples
A-N are known.
Example 49
[0257] The ability of the compounds of the present invention to
bind to TAAR1 was demonstrated in accordance with the test given
hereinafter.
Materials and Methods
Construction of TAAR Expression Plasmids and Stably Transfected
Cell Lines
[0258] For the construction of expression plasmids, the coding
sequences of human, rat and mouse TAAR 1 were amplified from
genomic DNA essentially as described by Lindemann et al. (2005)
Genomics 85, 372-385. The Expand High Fidelity PCR System (Roche
Diagnostics) was used with 1.5 mM Mg.sup.2+ and purified PCR
products were cloned into pCR2.1-TOPO cloning vector (Invitrogen)
following the instructions of the manufacturer. PCR products were
subcloned into the pIRESneo2 vector (BD Clontech, Palo Alto,
Calif.), and expression vectors were sequence verified before
introduction in cell lines.
[0259] HEK293 cells (ATCC # CRL-1573) were cultured essentially as
described in Lindemann et al. (2005) Genomics 85, 372-385. For the
generation of stably transfected cell lines, HEK293 cells were
transfected with the pIRESneo2 expression plasmids containing the
TAAR coding sequences (described above) with Lipofectamine 2000
(Invitrogen) according to the instructions of the manufacturer, and
24 hours post transfection, the culture medium was supplemented
with 1 mg/ml G418 (Sigma, Buchs, Switzerland). After a culture
period of about 10 days, clones were isolated, expanded and tested
for responsiveness to trace amines (all compounds purchased from
Sigma) with the cAMP Biotrak Enzyme immunoassay (EIA) System
(Amersham) following the non-acetylation EIA procedure provided by
the manufacturer. Monoclonal cell lines which displayed a stable
EC.sub.50 for a culture period of 15 passages were used for all
subsequent studies.
Membrane Preparation and Radioligand Binding
[0260] Cells at confluence were rinsed with ice-cold phosphate
buffered saline without Ca.sup.2+ and Mg.sup.2+ containing 10 mM
EDTA and pelleted by centrifugation at 1000 rpm for 5 minutes at
4.degree. C. The pellet was then washed twice with ice-cold
phosphate buffered saline and the cell pellet was frozen
immediately by immersion in liquid nitrogen and stored until use at
-80.degree. C. The cell pellet was then suspended in 20 ml
HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA, and homogenized
with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 seconds.
The homogenate was centrifuged at 48,000.times.g for 30 minutes at
4.degree. C. and the pellet resuspended in 20 ml HEPES-NaOH (20
mM), pH 7.4 containing 0.1 mM EDTA (buffer A), and homogenized with
a Polytron at 10,000 rpm for 10 seconds. The homogenate was then
centrifuged at 48,000.times.g for 30 minutes at 4.degree. C. and
the pellet resuspended in 20 ml buffer A, and homogenized with a
Polytron at 10,000 rpm for 10 seconds. Protein concentration was
determined by the method of Pierce (Rockford, Ill.). The homogenate
was then centrifuged at 48,000.times.g for 10 minutes at 4.degree.
C., resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl.sub.2
(10 mM) and CaCl.sub.2 (2 ml) (buffer B) at 200 .mu.g protein per
ml and homogenized with a Polytron at 10,000 rpm for 10
seconds.
[0261] Binding assay was performed at 4.degree. C. in a final
volume of 1 ml, and with an incubation time of 30 minutes. The
radioligand
[.sup.3H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline was
used at a concentration equal to the calculated K.sub.d value of 60
nM to give a total binding at around 0.1% of the total added
radioligand concentration, and a specific binding which represented
approximately 70-80% of the total binding. Non-specific binding was
defined as the amount of
[.sup.3H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline bound
in the presence of the appropriate unlabelled ligand (10 .mu.M).
Competing ligands were tested in a wide range of concentrations (10
.mu.M-30 .mu.M). The final dimethylsulphoxide concentration in the
assay was 2%, and it did not affect radioligand binding. Each
experiment was performed in duplicate. All incubations were
terminated by rapid filtration through UniFilter-96 plates (Packard
Instrument Company) and glass filter GF/C, pre-soaked for at least
2 hours in polyethylenimine 0.3%, and using a Filtermate 96 Cell
Harvester (Packard Instrument Company). The tubes and filters were
then washed 3 times with 1 ml aliquots of cold buffer B. Filters
were not dried and soaked in Ultima gold (45 .mu.l/well, Packard
Instrument Company) and bound radioactivity was counted by a
TopCount Microplate Scintillation Counter (Packard Instrument
Company).
[0262] The preferred compounds show a Ki value (.mu.M) in mouse on
TAAR1 in the range of <0.1 .mu.M as shown in the table
below.
TABLE-US-00001 Ki (.mu.M) Example mouse Example Ki 1 0.0609 39
0.0684 5 0.0059 42 0.0041 8 0.0843 46 0.0146 11 0.0025 47 0.0103 12
0.0097 13 0.0106 14 0.0606 16 0.0172 17 0.0019 20 0.043 35 0.0889
36 0.0227 37 0.0802
Example 50
TABLE-US-00002 [0263] Tablet Formulation (Wet Granulation)
mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of
formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3.
Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5.
Magnesium Stearate 1 1 1 1 Total 167 167 167 831
Manufacturing Procedure
[0264] 1. Mix items 1, 2, 3 and 4 and granulate with purified
water. 2. Dry the granules at 50.degree. C. 3. Pass the granules
through suitable milling equipment. 4. Add item 5 and mix for three
minutes; compress on a suitable press.
Example 52
TABLE-US-00003 [0265] Capsule Formulation mg/capsule Item
Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25
100 500 2. Hydrous Lactose 159 123 148 -- 3. Corn Starch 25 35 40
70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200
300 600
Manufacturing Procedure
[0266] 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable
capsule.
* * * * *