Note: Descriptions are shown in the official language in which they were submitted.
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1 H-IMIDAZOLE DERIVATIVES AS CANNABINOID CB2 RECEPTOR
MODULATORS
The present invention relates to a group of 1 H-imidazole derivatives which
are modulators of
cannabinoid CB2 receptors, to methods for the preparation of these compounds,
to novel
intermediates useful for the synthesis of said imidazole derivatives. The
invention also
relates to the use of a compound disclosed herein for the manufacture of a
medicament
giving a beneficial effect. A beneficial effect is disclosed herein or
apparent to a person
skilled in the art from the specification and general knowledge in the art.
The invention also
relates to the use of a compound of the invention for the manufacture of a
medicament for
treating or preventing a disease or condition. More particularly, the
invention relates to a new
use for the treatment of a disease or condition disclosed herein or apparent
to a person
skilled in the art from the specification and general knowledge in the art. In
embodiments of
the invention specific compounds disclosed herein are used for the manufacture
of a
medicament useful in the treatment of disorders in which cannabinoid CB2
receptors are
involved, or that can be treated via manipulation of those receptors.
1 H-Imidazole derivatives as CB1 receptor modulators are known from WO
03/027076, WO
03/063781, WO 03/040107 and WO 03/007887. (Morpholin-4-yl)alkyl-(1H)-imidazole
derivatives have been claimed as CB2 receptor modulators in WO 01/58869
disclosing three
specific imidazoles (examples 64, 65 and 66) all containing a n L-
phenylaianine derived
carboxamide group at the 4-position of their (1 H)-imidazole moiety. 1-Aryl-(1
H)-imidazole
derivatives have been claimed in US 4,952,698 as CNS active compounds. Recent
advances in the field of CB2 receptor selective ligands have been reviewed by
K.H. Raitio et
al. (Curr. Med. Chem. 2005, 12, 1217-1237).
Surprisingly, novel 1 H-imidazole derivatives have been found which bind to
the CB 2
receptor, including compounds having approximately hundred-fold higher CB2
receptor
affinities as compared to the prior art compounds which were exemplified in WO
01/58869.
Moreover, many of the compounds within this invention are highly CB2 receptor
subtype
selective which means that they bind with a much higher affinity to the CB2
receptor than to
the CB1 receptor. The compounds within this invention are either CB2 receptor
agonists, CB2
receptor partial agonists, CB2 receptor antagonists or CB2 receptor inverse
agonists.
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The invention relates to compounds of the general formula (I)
R4
Ri- N R3 (I)
I
R2
wherein:
- R, represents a hydrogen or halogen atom or a C,_3-alkyl group, which C,_3-
alkyl group
may contain 1-3 fluoro atoms or a hydroxy or amino group, or R, represents a
C2_3-
alkynyl group, a C2_3-alkenyl group, which C2_3-alkynyl group or C2_3-alkenyl
group may
contain 1-3 fluoro atoms, or R, represents an acetyl, cyclopropyl, cyano,
methylsulfonyl,
ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl,
methylsulfanyl,
ethylsulfanyl group, formyl group or a C2_4-heteroalkyl group,
- R2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5
substituents
Y, which can be the same or different, selected from the group consisting of
methyl,
ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro,
trifluoromethyl,
trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2
represents a
heteroaryl group which heteroaryl group may be substituted with 1, 2 or 3
substituents Y,
wherein Y has the meaning as defined above, with the proviso that R2 is not a
6-methyl-
2-pyridyl group, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic carbocyclic ring system, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or
heterocyclic ring
system may be substituted with 1-5 substituents selected from methyl, ethyl,
amino,
hydroxy or fluoro, or
R2 represents a group of general formula CH2-R5 wherein R5 represents a phenyl
group
which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or
R5 represents
a heteroaryl group or a 1,2,3,4-tetrahydronaphtyl or indanyl group, which
heteroaryl
group or 1,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1,
2 or 3
substituents Y as defined above or R5 represents a mono-unsaturated or fully
saturated
monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring
system, or
R5 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or
heterocyclic ring
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WO 2006/087355 PCT/EP2006/060009
systems are optionally substituted with 1 -5 substituents selected from the
group
consisting of methyl, ethyl, amino, hydroxy or fluoro, or
R2 represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a
acetamidoalkyl
group,
- R3 represents a hydrogen or halogen atom or a formyl, C,-6-alkylsulfonyl, C1-
6-
alkylsulfinyl, C,-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or
cyano group, or
R3 represents C,-$-alkyl group, which C,-$-alkyl group may be substituted with
1-5
substituents selected from the group consisting of fluoro, hydroxy or amino,
or R3
represents a C2-6-alkynyl, C2-6-alkenyl, C,-6-alkanoyl, C3-$-cycloalkyl, C5-$-
heterocycloalkyl
or a C2-6-heteroalkyl group, which groups are optionally substituted with 1-3
methyl
groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R3
represents a
phenyl group which is substituted with 1-5 substituents Y, wherein Y has the
meaning as
defined above, or R3 represents a heteroaryl group which heteroaryl group may
be
substituted with 1, 2 or 3 substituents Y, wherein Y has the meaning as
defined above or
R3 represents a benzyl or heteroarylmethyl group which benzyl or
heteroarylmethyl
group may be substituted with 1, 2 or 3 substituents Y
- R4 represents one of the subgroups (i) or (ii)
0 0
J, / R'
R6 N \R$
(i) (ii)
wherein R6 represents a C4-$ branched or linear alkyl group, C3-$ cycloalkyl
group, C3-$-
cycloalkyl-C,-2-alkyl group, C5-,-heterocycloalkyl-C,-2-alkyl group, C5-10
bicycloalkyl group,
C5-,o-bicycloalkyl-C,-2-alkyl group, C5-,o-heterobicycloalkyl-C,-2-alkyl
group, C6-10
tricycloalkyl group, C6-,o-tricycloalkyl-C,-2-alkyl group, C6-,o-
heterotricycloalkyl-C,-2-alkyl
group which groups may be substituted with 1-5 substituents selected from
methyl,
hydroxy, ethyl, trifluoromethyl or fluoro, or R6 represents a phenyl, benzyl,
napthyl or
phenethyl group which groups may be substituted on their aromatic ringsystem
with 1-3
substituents Y as defined above, with the proviso that R6 is not a 2-
methylphenyl group,
or R6 represents a pyridyl or thienyl group,
- R7 represents a hydrogen atom or a C,-6 linear alkyl group which C,-6 linear
alkyl group
may be substituted with 1-3 fluoro atoms or R7 represents an isopropyl group,
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WO 2006/087355 PCT/EP2006/060009
R8 represents a C2-6 alkyl group which group is substituted with a hydroxy or
amino
group or with 1-3 fluoro atoms, or R8 represents a C,-,o branched alkyl group,
C3-$
cycloalkyl group, C5-$ heterocycloalkyl group, C3-$-cycloalkyl-C,-2-alkyl
group, C5-,-
heterocycloalkyl-C,-2-alkyl group, C5-10 bicycloalkyl group, C5-,o-
bicycloalkyl-C,-2-alkyl
group, C5-,o-heterobicycloalkyl-C,-2-alkyl group, C6-10 tricycloalkyl group,
C6-10-
tricycloalkyl-C,-2-alkyl group, C6-,o-heterotricycloalkyl-C,-2-alkyl group
which groups may
be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl,
amino,
hydroxymethyl, trifluoromethyl or fluoro, or R8 represents a phenyl group
which group is
substituted with 1-5 substituents Y as defined above, or R8 represents a
naphtyl, 1,2,3,4-
tetrahydronaphtyl or indanyl group which naphtyl, 1,2,3,4-tetrahydronaphtyl or
indanyl
groups may be substituted with 1-3 substituents Y, or R8 represents a phenyl-
C,-3-alkyl
group, a diphenyl-C,-3-alkyl group, which groups may be substituted on their
phenyl ring
with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R8
represents a
benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R8
represents
a heteroaryl, heteroarylmethyl, napthylmethyl or heteroaryiethyl group, which
heteroaryl,
heteroarylmethyl, naphtylmethyl or heteroaryiethyl group may be substituted
with 1-3
substituents Y, wherein Y has the abovementioned meaning, or R8 represents a
piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-
hydroxypiperidinyl or
pyrrolidinyl group, with the proviso that R8 is neither a 6-methoxy-
benzothiazol-2-yl group
nor a [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,
or R7 and R8 - together with the nitrogen atom to which they are bonded - form
a
saturated or unsaturated, non-aromatic or partly aromatic, monocyclic,
bicyclic or tricyclic
heterocyclic group having 7 to 10 ring atoms, which saturated or unsaturated,
non-
aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic
group may be
substituted with 1-5 substituents selected from the group consisting of C,-3
alkyl, hydroxy,
methoxy, cyano, phenyl, trifluoromethyl or halogen,
or R7 and R8 - t ogether with the nitrogen atom to which they are bonded -
form a
saturated monocyclic heterocyclic group, optionally containing another
heteroatom
(selected from N, 0, S), having 5 to 6 ring atoms, which heterocyclic group is
substituted
with 1-5 substituents selected from the group consisting of C,-3 alkyl,
hydroxy, amino,
phenyl, benzyl, or fluoro,
with the proviso that R7 and R8 - together with the nitrogen atom to which
they are
bonded - do not form a trimethyl-substituted aza-bicyclo[3.2. 1 ]octanylgroup,
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and tautomers, stereoisomers and N-oxides thereof, as well as pharmaco-
logically
acceptable salts, hydrates and solvates of said compounds of formula (1) and
its tautomers,
stereoisomers and N-oxides.
5 The invention relates to racemates, mixtures of diastereomers as well as the
individual
stereoisomers of the compounds having formula (I).
In the description of the substituents the abbreviation 'alkyl' means a linear
or branched
alkyl group. For example, C,_3-alkyl m eans methyl, ethyl, n-propyl or
isopropyl. The
abbreviation 'heteroaryl' means monocyclic or fused bicyclic heteroaromatic
groups,
including but not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-
triazinyl, indazolyl,
indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, 1,3-
benzodioxolyl, 2,3-
dihydro-1,4-benzodioxinyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,
isochinolyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chinolyl,
phtalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, with the exclusion of the
quinolin-2-one group.
The abbreviation 'halogen' means chloro, fluoro, bromo or iodo. The
abbreviation 'C3-$-
cycloalkyl' means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl or cyclooctyl.
The abbreviation 'C5-$ heterocycloalkyl' refers to (N, 0, S) heteroatom
containing rings,
including but not limited to piperidinyl, morpholinyl, azepanyl, pyrrolidinyl,
thiomorpholinyl,
piperazinyl, tetrahydrofuryl, tetrahydropyranyl. The abbreviation 'C5-70
bicycloalkyl group'
refers to carbo-bicyclic ring systems, including but not limited to
bicyclo[2.2.1]heptanyl,
bicyclo[3.3.0]octanyl or the bicyclo[3.1.1]heptanyl group. The abbreviation
'Cs-10
tricycloalkyl group' refers to carbo-tricyclic ring systems such as the 1-
adamantyl,
noradamantyl or the 2-adamantyl group. The abbreviation 'CZ-4 heteroalkyl'
refers to (N, 0,
S) heteroatom containing linear or branched C2-4-alkyl groups, including but
not limited to
methoxymethyl, dimethylaminomethyl and ethylsulfanylmethyl.
Prodrugs of the compounds mentioned above are in the scope of the present
invention.
Prodrugs are therapeutic agents which are inactive per se but are transformed
into one or
more active metabolites. Prodrugs are bioreversible derivatives of drug
molecules used to
overcome some barriers to the utility of the parent drug molecule. These
barriers include, but
are not limited to, solubility, permeability, stability, presystemic
metabolism and targeting
limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-
494-5, Ed.: F.
D. King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther.
Patents, 14(3), 277-
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WO 2006/087355 PCT/EP2006/060009
280, 2004; P. Ettmayer et al., "Lessons leamed from marketed and
investigational prodrugs",
J. Med. Chem., 47, 2393-2404, 2004). Pro-drugs, i.e. compounds which when
administered
to humans by any known route, are metabolised to compounds having formula (I),
belong to
the invention. In particular this relates to compounds with primary or
secondary amino or
hydroxy groups. Such compounds can be reacted with organic acids to yield
compounds
having formula (I) wherein an additional group is present which is easily
removed after
administration, for instance, but not limited to amidine, enamine, a Mannich
base, a
hydroxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative,
carbamate,
ester, amide or enaminone.
N-oxides of the compounds mentioned above are in the scope of the present
invention.
Tertiary amines may or may not give rise to N-oxide metabolites. The extend to
what N-
oxidation takes place varies from trace amounts to a near quantitative
conversion. N-oxides
may be more active than their corresponding tertiary amines or less active.
Whilst N-oxides
are easily reduced to their corresponding tertiary amines by chemical means,
in the human
body this happens to varying degrees. Some N-oxides undergo nearly
quantitative reductive
conversion to the corresponding tertiary amines, in other cases the conversion
is a mere
trace reaction or even completely absent. (M.H. Bickel: "The pharmacology and
Biochemistry of N-oxides", Pharmacological Reviews, 21(4), 325 - 355, 1969).
The invention particularly relates to compounds of the general formula (1):
R4
Ri- N R3 (I)
I
R2
wherein:
- R, represents a halogen atom or a C,_3-alkyl group, which C,_3-alkyl group
may contain
1-3 fluoro atoms or a hydroxy or amino group, or R, represents a C2_3-alkynyl
group, a
C2_3-alkenyl group, which C2_3-alkynyl group or C2_3-alkenyl group may contain
1-3 fluoro
atoms, or R, represents an acetyl, cyclopropyl, cyano, methylsulfonyl,
ethylsulfonyl,
methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl,
ethylsulfanyl group,
formyl group or a C2_4-heteroalkyl group, and R2, R3 and R4 have the meanings
as given
above.
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More in particular, the invention relates to compounds of formula (I):
R4
Ri- N R3 (I)
I
R2
wherein:
- R3 represents a hydrogen or halogen atom or a formyl, methylsulfonyl,
ethylsulfonyl,
methylsulfinyl, ethylsulfinyl, trifluoromethylsulfanyl, methylsulfanyl,
ethylsulfanyl or cyano
group, or R3 represents C,-6-alkyl group, which C,-6-alkyl group may contain 1-
3 fluoro
atoms or a hydroxy or amino group, or R3 represents a C2-6-alkynyl, C2-6-
alkenyl, C1-6-
alkanoyl, C3-$-cycloalkyl, C5-$-heterocycloalkyl or a C2-6-heteroalkyl group,
which groups
are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy
group or
with 1-3 fluoro atoms, or R3 represents a phenyl group which is substituted
with 1-5
substituents Y, wherein Y has the meaning as defined above, or R3 represents a
heteroaryl group which heteroaryl group may be substituted with 1, 2 or 3
substituents Y,
wherein Y has the meaning as defined above or R3 represents a benzyl or
heteroarylmethyl group which benzyl or heteroarylmethyl group may be
substituted with
1, 2 or 3 substituents Y
- R4 represents subgroup (ii)
0
J, /R7
N
\R$
(ii)
wherein
- R7 represents a hydrogen atom or a C,-6 linear alkyl group or an isopropyl
group,
- R8 represents a C2-6 alkyl group which group is substituted with a hydroxy
or amino
group or with 1-3 fluoro atoms, or R8 represents a C,-,o branched alkyl group,
C3-$
cycloalkyl group, C5-$ heterocycloalkyl group, C3-$-cycloalkyl-C,-2-alkyl
group, C5-,-
heterocycloalkyl-C,-2-alkyl group, C5-10 bicycloalkyl group, C5-,o-
bicycloalkyl-C,-2-alkyl
group, C5-,o-heterobicycloalkyl-C,-2-alkyl group, C6-10 tricycloalkyl group,
C6-10-
tricycloalkyl-C,-2-alkyl group, C6-,o-heterotricycloalkyl-C,-2-alkyl group
which groups may
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WO 2006/087355 PCT/EP2006/060009
be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl,
amino,
hydroxymethyl, trifluoromethyl, or fluoro, or R8 represents a phenyl group
which group is
substituted with 1-5 substituents Y as defined above, or R8 represents a
naphtyl or a
1,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted
with 1-3
substituents Y, or R8 represents a phenyl-C,_3-alkyl group, a diphenyl-C,_3-
alkyl group,
which groups may be substituted on their phenyl ring with 1-5 substituents Y,
wherein Y
has the abovementioned meaning, or R8 represents a benzyl group, which benzyl
group
is substituted with 1-5 substituents Y, or R8 represents a heteroaryl,
heteroarylmethyl or
heteroaryiethyl group, which heteroaryl, heteroarylmethyl or heteroaryiethyl
group may
be substituted with 1-3 substituents Y, as defined above, or R8 represents a
piperidinyl,
azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or
pyrrolidinyl
group, with the proviso that R8 is neither a 6-methoxy-benzothiazol-2-yl group
nor a[3-
chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,
or R7 and R8 - together with the nitrogen atom to which they are bonded - form
a
saturated or unsaturated, non-aromatic or partly aromatic, monocyclic,
bicyclic or tricyclic
heterocyclic group having 7 to 10 ring atoms, which heterocyclic group may be
substituted with one or two C,_3 alkyl groups, a hydroxy group, a phenyl
group, a
trimethylfluoromethyl group, a benzyl group, a diphenylmethyl group or a
halogen atom,
or R7 and R8 - together with the nitrogen atom to which they are bonded - form
a
saturated monocyclic heterocyclic group, optionally containing another
heteroatom
(selected from N, 0, S), having 5 to 6 ring atoms, which heterocyclic group is
substituted
with 1-3 C,_3 alkyl groups, a hydroxy group or 1-2 fluoro atoms,
with the proviso that R7 and R8 - together with the nitrogen atom to which
they are
bonded - do not form a trimethyl-substituted aza-bicyclo[3.2.1]octanylgroup,
and R, and R2 have the meanings as given above.
Also more in particular the invention relates to compounds of formula (I)
R4
Ri- N R3 (I)
I
R2
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wherein:
- R, represents a halogen atom or a C,_3-alkyl group, which C,_3-alkyl group
may contain 1-
3 fluoro atoms or a hydroxy group, or R, represents a C2_3-alkynyl group, a
C2_3-alkenyl
group, acetyl, cyclopropyl, cyano, methylsulfonyl, methylsulfinyl,
methylsulfanyl or a C2_4-
heteroalkyl group,
- R2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5
substituents
Y, which can be the same or different, selected from the group consisting of
methyl,
ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro,
trifluoromethyl,
trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2
represents a
monocyclic heteroaryl group which heteroaryl group may be substituted with 1,
2 or 3
substituents Y, wherein Y has the meaning as defined above, with the proviso
that R2 is
not a 6-methyl-2-pyridyl group, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic carbocyclic ring system, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or
heterocyclic ring
system may be substituted with 1-5 substituents selected from methyl, ethyl,
amino,
hydroxy or fluoro, or
R2 represents a group of general formula CH2-R5 wherein R5 represents a phenyl
group
which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or
R5 represents
a heteroaryl group or a 1,2,3,4-tetrahydronaphtyl or indanyl group, which
heteroaryl
group or 1,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1,
2 or 3
substituents Y as defined above or R5 represents a mono-unsaturated or fully
saturated
monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring
system, or
R5 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or
heterocyclic rings
systems are optionally substituted with 1-3 methyl groups, an ethyl, amino or
hydroxy
group or with a fluoro atom,
- R3 represents a hydrogen or halogen atom or a methylsulfanyl or cyano group,
or R3
represents C,_6-alkyl group, which C,_6-alkyl group may contain 1-3 fluoro
atoms or a
hydroxy or amino group, or R3 represents a C2_6-alkynyl or C2_6-alkenyl group,
which
groups are optionally substituted with 1-3 fluoro atoms,
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R4 represents subgroup (ii)
0
J, /R7
N
\R$
(ii)
wherein
R7 represents a hydrogen atom or a C,-3 linear alkyl group,
5 - R8 represents a C2-6 alkyl group which group is substituted with a hydroxy
or amino
group or with 1-3 fluoro atoms, or R8 represents a C,-,o branched alkyl group,
C3-$
cycloalkyl group, C5-$ heterocycloalkyl group, C3-$-cycloalkyl-C,-2-alkyl
group, C5-,-
heterocycloalkyl-C,-2-alkyl group, C5-10 bicycloalkyl group, C5-,o-
bicycloalkyl-C,-2-alkyl
group, C5-,o-heterobicycloalkyl-C,-2-alkyl group, C6-10 tricycloalkyl group,
C6-10-
10 tricycloalkyl-C,-2-alkyl group, C6-,o-heterotricycloalkyl-C,-2-alkyl group
which groups may
be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl,
amino,
hydroxymethyl, trifluoromethyl or fluoro, or R8 represents a phenyl group
which group is
substituted with 1-5 substituents Y as defined above, or R8 represents a
naphtyl or a
1,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted
with 1-3
substituents Y, or R8 represents a phenyl-C,-3-alkyl group, a diphenyl-C,-3-
alkyl group,
which groups may be substituted on their phenyl ring with 1-5 substituents Y,
wherein Y
has the abovementioned meaning, or R8 represents a benzyl group, which benzyl
group
is substituted with 1-5 substituents Y, or R8 represents a heteroaryl,
heteroarylmethyl or
heteroaryiethyl group, which heteroaryl, heteroarylmethyl or heteroaryiethyl
group may
be substituted with 1-3 substituents Y, as defined above, or R8 represents a
piperidinyl,
azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or
pyrrolidinyl
group, with the proviso that R8 is neither a 6-methoxy-benzothiazol-2-yl group
nor a[3-
chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,
Even more particular the invention relates to compounds of formula (I)
R4
Ri- N R3 (I)
I
R2
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wherein:
- R, represents a halogen atom or a C,-3-alkyl group, which C,-3-alkyl group
may contain 1-
3 fluoro atoms or a hydroxy group, or R, represents a cyano, or methylsulfanyl
group,
- R2 represents a mono-unsaturated or fully saturated 5-7 membered monocyclic
carbocyclic ring system which may be substituted with 1-5 substituents
selected from
methyl, ethyl, amino, hydroxy or fluoro or R2 represents a phenyl group which
may be
substituted with 1, 2, 3, 4 or 5 substituents Y, which can be the same or
different,
selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy,
hydroxy,
chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy,
methylsulfonyl, carbamoyl,
phenyl and cyano,
- R3 represents a hydrogen or halogen atom or a methylsulfanyl or cyano group,
or R3
represents C,-6-alkyl group, which C,-6-alkyl group may contain 1-3 fluoro
atoms or a
hydroxy or amino group,
- R4 represents subgroup (ii)
0
J, /R7
N
\R$
(ii)
wherein
- R7 represents a hydrogen atom or a methyl group,
- R8 represents a C2-6 alkyl group which group is substituted with 1-3 fluoro
atoms, or R8
represents a C,-,o branched alkyl group, C3-$ cycloalkyl group, C5-$
heterocycloalkyl
group, C3-$-cycloalkyl-C,-2-alkyl group, C5-,-heterocycloalkyl-C,-2-alkyl
group, C5-10
bicycloalkyl group, C5-,o-bicycloalkyl-C,-2-alkyl group, C5-,o-
heterobicycloalkyl-C,-2-alkyl
group, C6-10 tricycloalkyl group, C6-,o-tricycloalkyl-C,-2-alkyl group, C6-10-
heterotricycloalkyl-C,-2-alkyl group which groups may be substituted with 1-5
substituents
selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or
fluoro, or
R8 represents a phenyl group which group is substituted with 1-5 substituents
Y as
defined above, or R8 represents a naphtyl or 1,2,3,4-tetrahydronaphtyl or
indanyl group
which groups may be substituted with 1-3 substituents Y, or R8 represents a
phenyl-C,-3-
alkyl group, a diphenyl-C,-3-alkyl group, which groups may be substituted on
their phenyl
ring with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R8
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
represents a substituted benzyl group, which benzyl group is substituted with
1-5
substituents Y, or R8 represents a heteroaryl, heteroarylmethyl or
heteroaryiethyl group,
which heteroaryl, heteroarylmethyl or heteroaryiethyl group may be substituted
with 1-3
substituents Y, as defined above, with the proviso that R8 is neither a 6-
methoxy-
benzothiazol-2-yl group nor a[3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl
group,
Most particular, the invention relates to compounds of formula (I)
R4
Ri- N R3 (I)
I
R2
wherein:
- R, represents a halogen atom or a C,-3-alkyl group, which C,-3-alkyl group
may contain 1-
3 fluoro atoms, or R, represents a cyano, or methylsulfanyl group,
- R2 represents a saturated six-membered monocyclic carbocyclic ring or R2
represents a
phenyl group which may be substituted with 1, 2 or 3 substituents Y, which can
be the
same or different, selected from the group consisting of methyl, ethyl,
propyl, methoxy,
ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl,
trifluoromethoxy,
methylsulfonyl, carbamoyl, phenyl and cyano,
- R3 represents a hydrogen or halogen atom or a methylsulfanyl or cyano group,
or R3
represents C,-4-alkyl group, which C,-4-alkyl group may contain 1-3 fluoro
atoms,
- R4 represents subgroup (ii)
0
J, / R7
N
\R$
(ii)
wherein
- R7 represents a hydrogen atom or a methyl group,
- R8 represents a C2-6 alkyl group which group is substituted with 1-3 fluoro
atoms, or R8
represents a C,-,o branched alkyl group, C3-$ cycloalkyl group, C5-$
heterocycloalkyl
group, C3-$-cycloalkyl-C,-2-alkyl group, C5-,-heterocycloalkyl-C,-2-alkyl
group, C5-10
bicycloalkyl group, C5-,o-bicycloalkyl-C,-2-alkyl group, C5-,o-
heterobicycloalkyl-C,-2-alkyl
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
group, C6-10 tricycloalkyl group, C6-,o-tricycloalkyl-C,-2-alkyl group, C6-10-
heterotricycloalkyl-C,-2-alkyl group, which groups may be substituted with 1-5
substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl,
trifluoromethyl
or fluoro, or R8 represents a phenyl group which group is substituted with 1-3
substituents Y, wherein Y has the meaning as defined above, or R8 represents a
naphtyl
group which group may be substituted with 1-3 substituents Y, or R8 represent
s a
phenyl-C,-2-alkyl group, which group may be substituted on the phenyl ring
with 1-3
substituents Y, wherein Y has the abovementioned meaning, or R8 represents a
substituted benzyl group, which benzyl group is substituted with 1-5
substituents Y
Finally, the invention also specifically relates to compounds having formula
(I) wherein
R2 represents a saturated six-membered monocyclic carbocyclic ring or R2
represents a
phenyl group which may be substituted with 1, 2, 3, 4 or 5 substituents Y,
which can be the
same or different, selected from the group consisting of methyl, ethyl,
propyl, methoxy,
ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl,
trifluoromethoxy, methylsulfonyl,
carbamoyl, phenyl and cyano, and all other symbols have the meanings as
described above.
In a further embodiment, the invention relates to compounds of the general
formula (XIV)
0
N z
R' N R3
R2
(XIV)
wherein:
- R, represents a halogen atom or a C,-3-alkyl group, which C,-3-alkyl group
may contain 1-
3 fluoro atoms or a hydroxy or amino group, or R, represents a C2-3-alkynyl
group, a C2-
3-alkenyl group, which C2-3-alkynyl group or C2-3-alkenyl group may contain 1-
3 fluoro
atoms, or R, represents an acetyl, cyclopropyl, cyano, methylsulfonyl,
ethylsulfonyl,
methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl,
ethylsulfanyl group,
formyl group or a C2-4-heteroalkyl group,
- R2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5
substituents
Y, which can be the same or different, selected from the group consisting of
methyl,
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro,
trifluoromethyl,
trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2
represents a
heteroaryl group which heteroaryl group may be substituted with 1, 2 or 3
substituents Y,
wherein Y has the meaning as defined above, with the proviso that R2 is not a
6-methyl-
2-pyridyl group, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic carbocyclic ring system, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or
heterocyclic ring
system may be substituted with 1-5 substituents selected from methyl, ethyl,
amino,
hydroxy or fluoro, or
R2 represents a group of general formula CH2-R5 wherein R5 represents a phenyl
group
which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or
R5 represents
a heteroaryl group or a 1,2,3,4-tetrahydronaphtyl or indanyl group, which
heteroaryl
group or 1,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1,
2 or 3
substituents Y as defined above or R5 represents a mono-unsaturated or fully
saturated
monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring
system, or
R5 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or
heterocyclic ring
systems are optionally substituted with 1-5 substituents selected from the
group
consisting of methyl, ethyl, amino, hydroxy or fluoro, or
R2 represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a
acetamidoalkyl
group,
With the proviso that R2 re presents not a phenyl, 4-methylphenyl or 4-
methoxyphenyl
group,
- R3 represents a hydrogen or halogen atom or a formyl, C,-6-alkylsulfonyl, C1-
6-
alkylsulfinyl, C,-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or
cyano group, or
R3 represents C,-$-alkyl group, which C,-$-alkyl group may be substituted with
1-5
substituents selected from the group consisting of fluoro, hydroxy or amino,
or R3
represents a C2-6-alkynyl, C2-6-alkenyl, C,-6-alkanoyl, C3-$-cycloalkyl, C5-$-
heterocycloalkyl
or a C2-6-heteroalkyl group, which groups are optionally substituted with 1-3
methyl
groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R3
represents a
phenyl group which is substituted with 1-5 substituents Y, wherein Y has the
meaning as
defined above, or R3 represents a heteroaryl group which heteroaryl group may
be
substituted with 1, 2 or 3 substituents Y, wherein Y has the meaning as
defined above or
CA 02597896 2007-08-14
WO 2006/087355 PCT/EP2006/060009
R3 represents a benzyl or heteroarylmethyl group which benzyl or
heteroarylmethyl
group may be substituted with 1, 2 or 3 substituents Y,
- Z represents a chloro atom or a C,_3 alkyl group, a hydroxy group, or a-O-
Na, -0-K, -0-
Li, or -0-Cs group, or Z represents a N-methoxy-N-methyl-amino group,
5 such compounds being useful in the synthesis of compounds of general formula
(I)
wherein:
- R, represents a halogen atom or a C,_3-alkyl group, which C,_3-alkyl group
may contain
1-3 fluoro atoms or a hydroxy or amino group, or R, represents a C2_3-alkynyl
group, a
C2_3-alkenyl group, which C2_3-alkynyl group or C2_3-alkenyl group may contain
1-3 fluoro
10 atoms, or R, represents an acetyl, cyclopropyl, cyano, methylsulfonyl,
ethylsulfonyl,
methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl,
ethylsulfanyl group,
formyl group or a C2_4-heteroalkyl group,
- R2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5
substituents
Y, which can be the same or different, selected from the group consisting of
methyl,
15 ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro,
trifluoromethyl,
trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2
represents a
heteroaryl group which heteroaryl group may be substituted with 1, 2 or 3
substituents Y,
wherein Y has the meaning as defined above, with the proviso that R2 is not a
6-methyl-
2-pyridyl group, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic carbocyclic ring system, or
R2 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or
heterocyclic ring
system may be substituted with 1-5 substituents selected from methyl, ethyl,
amino,
hydroxy or fluoro, or
R2 represents a group of general formula CH2-R5 wherein R5 represents a phenyl
group
which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or
R5 represents
a heteroaryl group or a 1,2,3,4-tetrahydronaphtyl or indanyl group, which
heteroaryl
group or 1,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1,
2 or 3
substituents Y as defined above or R5 represents a mono-unsaturated or fully
saturated
monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring
system, or
R5 represents a mono-unsaturated or fully saturated 4-10 membered monocyclic,
fused
bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or
heterocyclic ring
systems are optionally substituted with 1-5 substituents selected from the
group
consisting of methyl, ethyl, amino, hydroxy or fluoro, or
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
R2 represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a
acetamidoalkyl
group,
- R3 represents a hydrogen or halogen atom or a formyl, C,-6-alkylsulfonyl, C1-
6-
alkylsulfinyl, C,-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or
cyano group, or
R3 represents C,-$-alkyl group, which C,-$-alkyl group may be substituted with
1-5
substituents selected from the group consisting of fluoro, hydroxy or amino,
or R3
represents a C2-6-alkynyl, C2-6-alkenyl, C,-6-alkanoyl, C3-$-cycloalkyl, C5-$-
heterocycloalkyl
or a C2-6-heteroalkyl group, which groups are optionally substituted with 1-3
methyl
groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R3
represents a
phenyl group which is substituted with 1-5 substituents Y, wherein Y has the
meaning as
defined above, or R3 represents a heteroaryl group which heteroaryl group may
be
substituted with 1, 2 or 3 substituents Y, wherein Y has the meaning as
defined above or
R3 represents a benzyl or heteroarylmethyl group which benzyl or
heteroarylmethyl
group may be substituted with 1, 2 or 3 substituents Y
GENERAL ASPECTS OF SYNTHESES
Compounds of formula (I) may be prepared by different methodologies. The
selection of the
particular method depends on factors such as the compatibility of functional
groups with the
reagents used, the possibility to use protecting groups, catalysts, activating
and coupling
reagents and the ultimate structural features present in the final compound
being prepared.
Imidazole derivatives can be obtained according to methods known. Relevant
articles are:
a) Gomez-Sanchez et al., J. Heterocyclic Chem. (1987), 24, 1757-1763.
b) Matsuura et al., J. Chem. Soc. Perkin Trans. 1(1991), 11, 2821-2826
c) Ueda et al., Tetrahedron Lett. (1988), 29, 4607-4610
d) Gupta et al., Eur. J. Med. Chem. (2004), 39, 805-814
e) Van Berkel et al. Tetrahedron Lett. (2004), 45, 7659-7662
f) Haberhauer and Rominger, Tetrahedron Lett. (2002), 43, 6335-6338
g) Dell'Erba et al., Tetrahedron (1997), 53, 2125-2136
h) Lipshutz et al., Tetrahedron Lett. (1992), 33, 5865-5868
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
Compounds of general formula (I) can be obtained according to the procedures
outlined in
Schemes 1 - 6.
O
z _ Ry0 ~ ~ N R 1 ) OH HO _ ~ R
~O NO
i R3 i
1
+ R,C(OR)3 R3 i 2) H30+
R3 NHR2 R
R2 2
(II) (III) (IV) (V)
HNR7RB, AIMe3 chlorinating
O O L agent
X
HO \ HNR~RB XN R1 HNR~RB CI \
~ R1 R3 N R ~ R1
R3 N coupling reagent I 3 i
Rz R2 R2
(V) (I) wherein X represents
subgroup (ii) (Va)
HNMe(OMe)
coupling reagent
O X
N
~
O~N /\ RsLi or RsMgBr R3 X N3-- R'
R~
R3 i R
z
R2 (I) wherein X represents
(VI) subgroup (i)
5
Scheme 1: The symbols R, - R8 have the meanings as given above on pages 2-5,
R9 and
R,o represent alkyl(C,_3)
Nitroenamine derivatives of general formula (II) can be prepared according to
the procedure
10 published by Gomez-Sanchez et al., J. Heterocyclic Chem. (1987), 24, 1757-
1763.
Nitroenamine derivatives of general formula (II) can be reacted with ortho-
esters of general
formula (I11) to give imidazole derivatives of general formula (IV) (Scheme
1). Subsequent
basic ester hydrolysis, for example using lithium hydroxide (LiOH), NaOH, KOH
or CsOH
can provide intermediate imidazolecarboxylic acid alkali salts, which can be
acidified by an
acid such as aqueous hydrochloride (HCI) to give imidazolecarboxylic acid
derivatives of
general formula (V). Compounds of general formula (IV) can be amidated with an
amine of
general formula R7R8NH into a compound of general formula (I) wherein X
represents
subgroup (ii) as defined above. Such amidations can be catalyzed by
trimethylaluminum
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
(CH3)3AI. (For more information on aluminum-mediated conversion of esters to
amides, see:
J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. (1982), 12, 989-993.).
Imidazolecarboxylic acid derivatives of general formula (V) or their
corresponding alkali salts
can be reacted with an amine of general formula R7R8NH into a compound of
general
formula (I) wherein X represents subgroup (ii) as defined above. This
particular reaction
preferably proceeds via activating and coupling methods such as formation of
an active
ester, or in the presence of a so-called coupling reagent, such as for
example, DCC, HBTU
(O-benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate),
TBTU, HOAt (N-
hydroxy-7-azabenzotriazole), PyBOP (benzotriazol-1-yloxytris(pyrrolidino)-
phosphonium
hexafluorophosphate), BOP, CIP (2-chloro-1,3-dimethylimidazolinium
hexafluorophos-
phate), 2-chloro-1,3-dimethylimidazolinium chloride, PyAOP (7-azabenzotriazol-
1 -
yloxytris(pyrrolidino)-phosphonium hexafluoro-phosphate) and the like. (For
more
information on activating and coupling methods see a) M. Bodanszky, A.
Bodanszky: The
Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-
57505-7; b) K.
Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318; c) F. Albericio et al.,
Tetrahedron Lett.
(1997), 38, 4853-4856); d) C. Montalbetti and V. Falque, Tetrahedron (2005),
61, 10827-
10852).
Alternatively, a compound having general formula (V) or the corresponding
alkali salts can
be reacted with a so-called halogenating agent such as for example thionyl
chloride (SOCI2)
or oxalyl chloride. This reaction gives the corresponding carbonyl chloride
(acid chloride)
(Va) which can subsequently be reacted with a compound having formula R7R8NH
wherein
R, and R$ have the meanings as described above, to give a compound of general
formula (I)
wherein X represents subgroup (ii) as defined above. Such reactions can be
catalyzed by
pyridine or 4-dimethylaminopyridine (DMAP).
A compound having general formula (V) can be reacted with N-methoxy-N-
methylamine in
the presence of a coupling reagent to yield the corresponding N-methoxy-N-
methylamide of
general formula (VI) and subsequently reacted with a lithium reagent of
general formula R6-
Li or a Grignard reagent to give a compound of general formula (I), wherein X
represents
subgroup (i) as defined above.
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
O O
R9O N R90 ~
R R~
/~Rj + L CH2R5 R:!~ N
a N I
H R2
(VII) (VIII) (IV) wherein R2 represents -CH2R5
J,R2B(OH)2
O
R,O ~ ~R
R3 N '
I
R2
(IV)
Scheme 2: The symbols R, - R5 have the meanings as given above as given above
on
pages 2-5, R9 represents alkyl(C,_3). In the compounds of general formula R2-
B(OH)2, R2
represents an optionally substituted phenyl or heteroaryl group, a so-called
Suzuki reagent.
Alternatively, a compound having general formula (VII) can be reacted with a
compound of
general formula (VIII), wherein L represents a so-called leaving group, such
as chloro,
bromo, iodo or mesyloxy (Scheme 2). A compound having general formula (VII)
can also be
reacted with a methylsulfonylaminoalkyl halogenide or methylsulfonylalkyl
halogenide to add
a methylsulfonylaminoalkyl group or methylsulfonylalkyl group to the 1-
position of the
imidazole nucleus. Such reactions are preferably carried out in the presence
of a base, such
as sodium hydride or potassium carbonate to facilitate the nucleophilic attack
of compound
(VII) to produce a compound of formula (IV), wherein R2 represents a group -
CH2R5 and R5
has the abovementioned meaning.
Alternatively, a compound having general formula (VII) can be reacted with
compound of
general formula R2-B(OH)2 wherein R2 represents an optionally substituted
phenyl or
heteroaryl group, a so-called Suzuki reagent, to produce a compound of general
formula
(IV). Compounds of general formula (IV) can be converted to compounds of
general formula
(I) according to Scheme 1. Such reactions may be metal-catalyzed.
CA 02597896 2007-08-14
WO 2006/087355 PCT/EP2006/060009
O p
O O NaN02 R O (R,CO)20 R3
R3 a OR ~pR9
~p acetic acid ~ 9 Pt/C, H21 EtOH
Rs N,~ HN
OH ~r_ R'
(IX)
(X) O
(XI)
(R~CO)20
Base
O O
O 1. KO-t-Bu R3 _4~ N ORs
_ OR9 2. R3COCI =HCI NH2
3. HCI
(XII) (XIII)
0
O p
N R
R3 R2NH2 R9p CN
OR9 ,
butyronitrile RHN~ R1 ~
R2
O
(XI) (IV)
Scheme 3: The symbols R, - R3 have the meanings as given above as given above
on
pages 2-5, R9 represents alkyl(C,_3)
5
A compoun d having general formula (IX) can be reacted with a nitrite
derivative such as
sodium nitrite (NaNO2) to give a compound of general formula (X). (Scheme 3).
A compound
having general formula (X) can be reacted with an anhydride of general formula
(R,CO)20 in
the presence of a reducing agent such as hydrogen and a catalyst such as Pd on
carbon
10 (Pd/C) and the like, in an inert organic solvent such as ethanol to give a
compound of
general formula (XI). A compound having general formula (XI) can be reacted
with an amine
of general formula R2NH2 in an inert solvent such as butyronitrile, to give a
compound of
general formula (IV). Compounds of general formula (IV) can be converted to
compounds of
general formula (I) according to Scheme 1.
15 Alternatively, a compound of general formula (XI) can be obtained in a two-
pot reaction from
a compound of general formula (XII). A compound of general formula (XII) can
be
deprotonated with a strong base such as potassium tert-butoxide (KO-t-Bu) and
subsequently reacted with an acylating compound of general formula R3COL,
wherein L
represents a leaving group such as chloride, followed by treatment with an
acid such as
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WO 2006/087355 PCT/EP2006/060009
hydrochloric acid and the like. The resulting compound of general formula
(XIII) can be
reacted with an anhydride of general formula (R,CO)20 to give a compound of
formula (XI).
Alternatively, a compound having general formula (X) can be reacted with a
reducing agent
such as hydrogen and a catalyst such as Pd on carbon (Pd/C) and the like, in
an inert
organic solvent such as ethanol in the presence of an acid such as
hydrochloric acid to give
a compound of general formula (XIII).
x x
N
H~ R1 LDA R Ri
Nr 3 I
I R3-L
R2 R2
(1) (1)
wherein X represent subgroup (ii) wherein X represent subgroup (ii)
Scheme 4: The symbols R, - R3 have the meanings as given above as given above
on
pages 2-5, X represents subgroup (ii).
A compound having general formula (I) wherein X represents subgroup (ii) and
wherein the
5-position of the imidazole moiety contains a hydrogen atom can be
deprotonated with a
strong non-nucleophilic base such as lithium diisopropylamide (LDA), followed
by treatment
with a group R3-L wherein L represents a leaving group to give a compound of
general
formula (I) wherein X represents subgroup (ii) and wherein the 5-position of
the imidazole
moiety contains a substituent R3 (Scheme 4).
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WO 2006/087355 PCT/EP2006/060009
0 0 0
-t~-
R,O ~\\ N 1) OH- HO N HNR7RB R7R8N N
I 2) H30' N coupling reagent N
R2 R2 R2
(IV) wherein R, and
R3 represent H (V) wherein R, and (I) wherein R, and
R3 represent H R3 represent H
0 O 0 0
R7R8N N
~ 1) n-BuLi R7R8N N R7R8N N R7R8N N N ~/
- J~~
2) EL E N + N~E + E N~E
R2 3) hydrolysis R2 R2 R2
(I) wherein R, and (I) wherein R, = H and (I) wherein R, = H and (I) wherein
R, and
R3 represent H R3 represents E R3 represents E R3 represent E
Scheme 5: The symbols R2, R7, R8 and R9 have the meanings as given above as
given
above on pages 2-5, E is derived from an electrophilic moiety, L represents a
leaving group.
An imidazole derivative of general formula (IV) wherein R, and R3 represent
hydrogen and
wherein R9 has the abovementioned meaning can be converted via ester
hydrolysis, for
example by using lithium hydroxide (LiOH), NaOH, KOH or CsOH to provide
intermediate
imidazolecarboxylic acid alkali salts, which salts can be acidified by an acid
such as aqueous
hydrochloride (HCI) to give imidazolecarboxylic acid derivatives of general
formula (V).
Imidazolecarboxylic acid derivatives of general formula (V) can be amidated to
give a
compound of general formula (I) wherein R, and R3 represent hydrogen and R2,
R7 and R8
have the abovementioned meaning. This compound of general formula (I) wherein
R, and R3
represent hydrogen and R 2, R, and R8 have the abovementioned meaning can be
deprotonated with a strong non-nucleophilic base such as lithium
diisopropylamide (LDA) or
n-Buli, followed by treatment with a group E-L wherein L represents a leaving
group, such as
iodide, bromide, or S-alkyl and E represents an electrophilic group, including
but not limited
to -S-alkyl, primary alkyl, chloro, bromo, iodo or cyano to give a compound of
general
formula (I) wherein X represents subgroup (ii) and wherein the 2/5-position of
the imidazole
moiety represent a substituent E and/or a hydrogen atom, depending on the type
of group E-
L applied in this reaction (Scheme 5). The definition of the group E is part
of the definition of
R, and R3 and does not exceed the definitions of R, and R3 given above. The
mixtures of
compounds that may be formed in the last reaction step in Scheme 5 can be
separated and
purified, for example by chromatographic methods or by crystallisation
techniques.
CA 02597896 2007-08-14
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WO 2006/087355 PCT/EP2006/060009
0 0 0
R7R8N N Br2 or CI2 R7R8N N Br2 or CIZ R'R8N N
N R3 /~ N R3 ~ NR1
R2 ~ R2
(I) wherein R, and (I) wherein R, = H and (I) wherein R, = CI or Br and
R3 represent H R3 represents CI or Br R3 represents CI or Br
Scheme 6: The symbols R2, R7, and R8 have the meanings as given above as given
above
on pages 2-5.
A compound of general formula (I) wherein R, and R3 represent hydrogen and R2,
R7 and
R8 have the abovementioned meaning can be reacted with a halogenating agent
such as N-
chlorosuccinimide (NCS) or bromine (Br2) in an inert organic solvent such as
dichloromethane to give a compound of general formula (I) wherein R3
represents Cl or Br
and R, represents a hydrogen atom. A compound of general formula (I) wherein
R3
represents Cl or Br and R, represents a hydrogen atom can be reacted with a
halogenating
agent such as NCS or Br2 in an inert organic solvent such as dichloromethane
to give a
compound of general formula (I) wherein R3 represents Cl or Br and R,
represents Cl or Br
(Scheme 6).
For more detailed information on nucleophiles, electrophiles and the leaving
group concept
see: M. B. Smith and J. March: Advanced organic chemistry, p. 275, 5th ed.,
(2001) John
Wiley & Sons, New York, ISBN: 0-471-58589-0). More information on addition and
subsequent removal of protective groups in organic synthesis can be found in:
T.W. Greene
and P.G.M. Wuts, "Protective Groups in Organic Synthesis", third edition, John
Wiley &
Sons, Inc., New York, 1999.
Pharmaceutically acceptable salts may be obtained using standard procedures
well known
in the art, for example by mixing a compound of the present invention with a
suitable acid,
for instance an inorganic acid such as hydrochloric acid, or with an organic
acid such as
fumaric acid.
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WO 2006/087355 PCT/EP2006/060009
PHARMACEUTICAL PREPARATIONS
The compounds of the invention can be brought into forms suitable for
administration by
means of usual processes using auxillary substances such as liquid or solid
carrier material.
The pharmaceutical compositions of the invention may be administered
enterally, orally,
parenterally (intramuscularly or intravenously), rectally or locally
(topically). They can be
administered in the form of solutions, powders, tablets, capsules (including
microcapsuies),
ointments (creams or gel) or suppositories. Suitable excipients for such
formulations are the
pharmaceutically customary liquid or solid fillers and extenders, solvents,
emulsifiers,
lubricants, flavorings, colorings and/or buffer substances. Frequently used
auxiliary
substances which may be mentioned are magnesium carbonate, titanium dioxide,
lactose,
mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin,
starch, cellulose and
its derivatives, animal and vegetable oils such as fish liver oil, sunflower,
groundnut or
sesame oil, polyethylene glycol and solvents such as, for example, sterile
water and mono-
or polyhydric alcohols such as glycerol.
Compounds of the present invention are generally administered as
pharmaceutical
compositions which are important and novel embodiments of the invention
because of the
presence of the compounds, more particularly specific compounds disclosed
herein. Types
of pharmaceutical compositions that may be used include but are not limited to
tablets,
chewable tablets, capsules, solutions, parenteral solutions, suppositories,
suspensions, and
other types disclosed herein or apparent to a person skilled in the art from
the specification
and general knowledge in the art. In embodiments of the invention, a
pharmaceutical pack or
kit is provided comprising one or more containers filled with one or more of
the ingredients of
a pharmaceutical composition of the invention. Associated with such
container(s) can be
various written materials such as instructions for use, or a notice in the
form prescribed by a
governmental agency regulating the manufacture, use or sale of pharmaceuticals
products,
which notice reflects approval by the agency of manufacture, use, or sale for
human or
veterinary administration.
PHARMACOLOGICAL METHODS
In vivo and in vitro pharmacological assays related to cannabinoid CB2
receptor
neurotransmission have been described in the literature. Some examples are:
0 Ibrahim, M.M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 10529-10533
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WO 2006/087355 PCT/EP2006/060009
= Hanus, L. et al. (1999) Proc. Natl. Acad. Sci. USA 96, 14228-14233
= Zhang, J. et al. (2003) Eur. J. Neuroscience 17, 2750-2754.
= Klein, T.W. et al. (2003) J. Leukoc. Biol. 74, 486-496
= Shoemaker, J.L. et al. (2005), J. Pharmacol. Exp. Ther. 315, 828-838
5 = Iwamura, H. et al. (2001), J. Pharmacol. Exp. Ther. 296, 420-425.
In vitro affinity for cannabinoid-CB, receptors
The affinity of the compounds of the invention for cannabinoid CB1 receptors
can be
10 determined using membrane preparations of Chinese hamster ovary (CHO) cells
in which
the human cannabinoid CB1 receptor is stably transfected in conjunction with
[3H]CP-55,940
as radioligand. After incubation of a freshly prepared cell membrane
preparation with the
[3H]-ligand, with or without addition of compounds of the invention,
separation of bound and
free ligand is performed by filtration over glassfiber filters. Radioactivity
on the filter is
15 measured by liquid scintillation counting.
In vitro affinity for cannabinoid-CB2 receptors
The affinity of the compounds of the invention for cannabinoid CB2 receptors
can be
20 determined using membrane preparations of Chinese hamster ovary (CHO) cells
in which
the human cannabinoid CB2 receptor is stably transfected in conjunction with
[3H]CP-55,940
as radioligand. After incubation of a freshly prepared cell membrane
preparation with the
[3H]-ligand, with or without addition of compounds of the invention,
separation of bound and
free ligand is performed by filtration over glassfiber filters. Radioactivity
on the filter is
25 measured by liquid scintillation counting.
Due to their cannabinoid CB2 receptor modulating activity the compounds
according to the
invention are suitable for use in the treatment of immune system disorders,
inflammatory
disorders, allergies, pain, neuropathic pain, multiple sclerosis,
neurodegenerative disorders,
dementia, dystonia, muscle spasticity, tremor, epilepsy, traumatic brain
injury, stroke,
Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease,
cerebral
ischaemia, cerebral apoplexy, craniocerebral trauma, spinal cord injury,
neuroinflammatory
disorders, brainstem neurodegeneration, plaque sclerosis, viral encephalitis,
demyelinisation
related disorders, and other neurological disorders as well as in the
treatment of cancers,
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WO 2006/087355 PCT/EP2006/060009
diabetes, gastric diseases, lung diseases, asthma and cardiovascular diseases
as well as
other diseases wherein CB2 receptor neurotransmission is involved.
The compounds of the invention can be brought into forms suitable for
administration by
means of usual processes using auxiliary substances and/or liquid or solid
carrier materials.
DOSE
The affinity of the compounds of the invention for cannabinoid CB2 receptors
was
determined as described above. From the binding affinity measured for a given
compound of
formula (I), one can estimate a theoretical lowest effective dose. At a
concentration of the
compound equal to twice the measured K;-value, 100% of the cannabinoid CB2
receptors
likely will be occupied by the compound. Converting that concentration to mg
of compound
per kg of patient yields a theoretical lowest effective dose, assuming ideal
bioavailability.
Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose
actually
administered to a higher or lower value. The dosage expediently administered
is 0.001 -
1000 mg/kg, preferably 0.1-100 mg/kg of patient's bodyweight.
TREATMENT
The term "treatment" as used herein refers to any treatment of a mammalian,
preferably
human condition or disease, and includes: (1) preventing the disease or
condition from
occurring in a subject which may be predisposed to the disease but has not yet
been
diagnosed as having it, (2) inhibiting the disease or condition, i.e.,
arresting its development,
(3) relieving the disease or condition, i.e., causing regression of the
condition, or (4) relieving
the conditions caused by the disease, i.e., stopping the symptoms of the
disease.
EXAMPLES
EXAMPLE 1: MATERIALS AND METHODS
All reactions involving moisture sensitive compounds or conditions were
carried out under an
anhydrous nitrogen atmosphere. Reactions were monitored by using thin-layer
chromatography (TLC) on silica coated plastic sheets (Merck precoated silica
gel 60 F254)
with the indicated eluent. Spots were visualised by UV light (254 nm) or 12.
Flash
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chromatography refers to purification using the indicated eluent and Acros
silica gel (0.030-
0.075 mm). Petroleum ether means petroleum ether 40-60. Nuclear magnetic
resonance
spectra ('H NMR and 13C NMR) were determined in the indicated solvent with
tetramethylsilane as an internal standard. Chemical shifts are given in ppm (b
scale)
downfield from tetra-methylsilane. Coupling constants J are given in hertz
(Hz). Peakshapes
in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (double
quartet), 't'
(triplet), 'dt' (double triplet), 'd' (doublet), 'dd' (double doublet), 's'
(singlet), 'br s' (broad
singlet) and 'm' (multiplet). Melting points were recorded on a Buchi B-545
melting point
apparatus or determined by a differential scanning calorimetry (DSC) method.
Yields refer to
isolated pure products.
Preparative LC/MS instrumentation and procedure
Sciex API 150 EX masspectrometer with electron spray,
2 Shimadzu LC8A LC pump,
Shimadzu SCL-10A VP system controller,
Shimadzu SPD-10A VP UV meter,
Gilson 215 injector/collector,
Column : Phenomenex Luna C18 (2)
150x21.2x5N
Eluant : A 100% Water + 0.1% Formic acid on pH=3
B 100% Acetonitrile + 0.1% Formic acid
Injection : 2.5 ml
Splitter : 1 to 50,000 with a make-up flow of 0.2 mI/min
(25% H20/75% ACN met 0.25% HCOOH)
MS scan : from 100 - 900 amu step 1 amu scan time 1 sec.
Method : Flow rates and gradient profiles.
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WO 2006/087355 PCT/EP2006/060009
Total Time (min) Flow rate (mI/min) A%(v/v) B%(v/v)
0 5 95 5
2 5 95 5
2.1 20 95 5
12 20 0 100
14 20 0 100
14.5 20 95 5
15 20 95 5
EXAMPLE 2: SYNTHESES OF SPECIFIC COMPOUNDS
The specific compounds of which the synthesis is described below are intended
to further
illustrate the invention in more detail, and therefore are not deemed to
restrict the scope of
the invention in any way. Other embodiments of the invention will be apparent
to those
skilled in the art from consideration of the specification and practice of the
invention
disclosed herein. It is thus intended that the specification and compounds be
considered as
exemplary only, with a true scope and spirit of the invention being indicated
by the claims.
Synthesis of compound 1
Part A: A magnetically stirred mixture of ethyl 5-methyl-1 H-imidazole-4-
carboxylate (13.875
g, 0.090 mol), phenylboronic acid (13.16 g, 0.108 mol) and Cul (0.85 g, 0.0045
mol) in
ethanol/water (900 ml, 1/1 (v/v)) was divided in 12 equal portions and reacted
in parallel at
85 C for 60 hours. After cooling to room temperature the 12 portions were
combined and
concentrated in vacuo. The residue was purified by flash chromatography
(Ethylacetate/petroleum ether 40-65 = 1/1 (v/v)) to give ethyl 5-methyl-1-
phenyl-1H-
imidazole-4-carboxylate (5.88 g, 26 % yield). 'H-NMR (400 MHz, CDCI3): b 1.42
(t, J = 7 Hz,
3H), 2.47 (s, 3H), 4.40 (q, J = 7 Hz, 2H), 7.26-7.31 (m, 2H), 7.48-7.56 (m,
3H), 7.59 (s, 1 H).
Part B: (-)-Cis-myrtanylamine (CAS 38235-68-6) (0.95 ml, 5.7 mmol) was
dissolved in
anhydrous dichloromethane (15 ml) and (CH3)3AI (2.9 ml of a 2 M solution in
heptane, 5.8
mmol) was added. The resulting mixture was magnetically stirred for 10 minutes
at room
temperature and ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (1.1 gram,
4.8 mmol)
was added. The resulting mixture was stirred at 35 C for 16 hours, poured
into an aqueous
NaHCO3 solution, stirred for 30 minutes and filtered over hyflo. The filtrate
was twice
extracted with dichloromethane. The organic layers were dried over Na2SO4,
filtered and
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WO 2006/087355 PCT/EP2006/060009
concentrated in vacuo. Subsequent purification with flash chromatography
(ethyl
acetate/petroleum ether 40-65 = 1/2 (v/v)) gave N-[(1R,2S,5R)-rel-6,6-
dimethylbicyclo[3.1.1]heptan-2-methyl]-5-methyl-1-phenyl-1 H-imidazole-4-
carboxamide,
compound 1 (1.05 gram, 65 % yield). Melting point: 85-89 C.
0
NH H
N
H
6
Compound 1
Analogously, the following compounds 2- 7 were prepared :
0
N~
H
N
6
Compound 2
Compound 2: Melting point: 214-219 C.
0
JL N
H
N 10 Compound 3
Compound 3: Melting point: 167-169 C.
0
NCjN
H
N
6
Compound 4
Compound 4: from R-(+)-bornylamine (CAS 32511-34-5). Melting point: 209-212
C.
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WO 2006/087355 PCT/EP2006/060009
0
N
N
b
Compound 5
Compound 5: from endo-(1 R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine.
Melting point:
149-152 C.
0
N~N
~ H
N
6
Compound 6
Compound 6: Melting point: 198-200 C.
0
N~N
-G
' H
N
b
Compound 7
Compound 7: Melting point: 232-234 C.
0
N~N~
II H
N
6
Compound 8
Synthesis of compound 8
Part A: Ethyl 2-methyl-l-phenyl-1H-imidazole-4-carboxylate (4.8 gram, 21 %
yield) was
prepared according to the procedure described (in J. Heterocyclic Chem. 1987,
24, 1757-
1763) from ethyl 3-anilino-2-nitro-acrylate (23.6 gram, 0.01 mol) and
triethylorthoacetate
(150 ml). The initially formed crude product was purified by flash
chromatography (eluent:
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WO 2006/087355 PCT/EP2006/060009
diethyl ether). Rf (diethylether - 0.15) to give pure ethyl 2-methyl-l-phenyl-
1H-imidazole-4-
carboxylate as an oil.
Part B: Ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate (2.25 gram, 0.012
mol) was
reacted (analogously to the procedure described hereinabove for compound 1)
with AIMe3
(7.2 ml of a 2M solution in hexane, 0.0144 mol) and 1-adamantane amine. HCI
(2.25 g,
0.012 mol). The initially formed crude product was purified by flash
chromatography (eluent:
diethyl ether) to give N-adamantyl-2-methyl-l-phenyl-1 H-imidazole-4-
carboxamide (2.2
gram, 55 % yield). Melting point: 207-210 C.
0
N~H~
N
H I-
Compound 9
~
Compound 9 was prepared analogously to compound 6 from (-)-cis-myrtanylamine
(CAS
38235-68-6). Melting point: 124-127 C.
0
N-[~D
N
b
Compound 10
Compound 10 : N-Adamantyl-2-methyl-l-phenyl-lH-imidazole-4-carboxamide (0.33
gram,
0.001 mol) was dissolved in anhydrous tetrahydrofuran (25 ml). The resulting
solution was
slowly added to a solution of lithium diisopropylamide (1.25 ml of a 2 M
solution in
heptane/THF, 0.0025 mol LDA) under N2 at -70 C. A solution of methyl iodide
(0.14 gram,
0.001 mol) in anhydrous THF was added and the resulting solution was stirred
for 1 hour at -
70 C. The solution was allowed to attain room temperature and stirred for
another 2 hours
and subsequently quenched with aqueous acetic acid. After concentration in
vacuo the
resulting residue was purified by flash chromatography (diethyl
ether/petroleum ether (40-60)
= 3/1 (v/v)) to give compound 10 and compound 11, respectively.
Melting point compound 10: 180-183 C.
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WO 2006/087355 PCT/EP2006/060009
0
II H
N~N-I~D
N
b
Compound 11
Compound 11: Compound 11 was prepared more efficiently by reacting ethyl 2,5-
dimethyl-1-
phenyl-1 H-imidazole-4-carboxylate (Cf. the corresponding methyl ester 3j in
J. Heterocyclic
Chem. 1987, 24, 1757-1763) with AIMe3 and 1-adamantane-amine.HCI, according to
the
Weinreb amidation procedure described hereinabove for compound 1, Part B.
Melting point: 201-204 C.
Synthesis of compound 12
Part A: Ethyl 2,5-dimethyl-l-(3-methoxyphenyl)-1H-imidazole-4-carboxylate was
prepared
analogously to the procedure described (in J. Heterocyclic Chem. 1987, 24,
1757-1763) from
ethyl 3-(3-methoxyphenylamino)-3-methyl-2-nitro-acrylate and
triethylorthoacetate.
Part B: Ethyl 2,5-dimethyl-1-(3-methoxyphenyl)-1H-imidazole-4-carboxylate was
amidated
(analogously to the procedure described hereinabove for compound 1) (stirred
at 70 C for
16 hours) with AIMe3 and (-)-cis-myrtanylamine (CAS 38235-68-6) to give
compound 12.
Melting point: 153-155 C.
0
H
H
N ~
N
H
Compound 12
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WO 2006/087355 PCT/EP2006/060009
Analogously were prepared compounds 13-20.
o ~-L0N O
H H N H~ N H~
N N
"
.HCI
Compound 13 Compound 14 Compound 15
m.p.: 156-158 C. m.p.: 214-216 C. m.p.: 190-193 C.
0 ci ci
0 N
0
~ ~H
\ II H N
N ~
~ H
i
~ ~~
\
N N ~
~
Compound 16 Compound 17 Compound 18
m.p.: 217-223 C m.p.: 216-218 C m.p.: 137-140 C.
0 0
N H~
N N
i
0' I
Compound 19 Compound 20
m.p.: 119-121 C. m.p.: 186-188 C.
Synthesis of compound 21
Part A: To a magnetically stirred suspension of ethyl 4-methyl-1 H-imidazole-5-
carboxylate
(15.42 gram, 0.100 mol) in anhydrous THF was slowly added sodium hydride (NaH)
(4.88 g
of a 60 % suspension, 0.120 mol) and the resulting mixture was stirred at room
temperature
for 30 minutes. Benzyl bromide (13.8 ml, 0.120 mol) was slowly added and the
resulting
mixture was reacted for 16 hours. Water was added to the mixture. The organic
layer was
separated from the water layer. The water layer was extracted 3 times with
ethylacetate. The
organic layer was dried over MgS04, filtered and thoroughly concentrated to
give an oil. The
resulting residue was purified (in order to separate the two formed
regioisomers) by flash
chromatography (diethyl ether/ethyl acetate gradient) to give ethyl N-benzyl-5-
methyl-1 H-
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WO 2006/087355 PCT/EP2006/060009
imidazole-4-carboxylate (11.4 gram, 47 % yield). 'H-NMR (400 MHz, CDCI3): b
1.40 (t, J = 7,
3H), 2.45 (s, 3H), 4.37 (q, J = 7, 2H), 5.10 (s, 2H), 7.03-7.08 (m, 2H), 7.28-
7.38 (m, 3H),
7.48 (s, 1 H).
Part B: Ethyl N-benzyl-5-methyl-1 H-imidazole-4-carboxylate (1.5 gram, 0.0061
mol) was
reacted with adamantyl-l-amine.HCI (1.72 g, 0.0092 mol) and AI(CH3)3 (4.6 ml.
2M in
hexane, 0.0092 mol) in 1,2-dichloroethane (20 ml) at 70 C for 40 hours
according to the
procedure described for compound 1, part B. Purification by flash
chromatography (ethyl
acetate/petroleum ether = 1/1 (v/v)) gave compound 21 (1.24 gram, 58 %).
Melting point:
182-184 C.
0
N~N
CI I~
N
0
Compound 21
Analogously were prepared compounds 22, 23 and 23A:
0
N~H H
~N
H
S N~
O H
Compound 22
Synthesis of compound 22
Compound 22 was prepared via the coupling of 3-(methylsulfonylamino)propyl
chloride with
ethyl 4-methyl-1 H-imidazole-5-carboxylate using K2CO3 as the base in DMF at
90 C for 20
hours, subsequent separation of the two formed regioisomers by flash
chromatography
(ethyl acetate/methanol = 9/1 (v/v)), followed by the AI(CH3)3 catalyzed
amidation with (-)-cis-
myrtanylamine.
Compound 22. Melting point: 84-108 C. Rf 0.35 (EtOAc/MeOH = 4/1 (v/v)).
0
N
H
N~
0 H
Compound 23
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WO 2006/087355 PCT/EP2006/060009
Compound 23. (from endo-(1R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine)
Melting point:
149-156 C. Rf 0.4 (EtOAc/MeOH = 4/1 (v/v)).
0
NC
j~H H
N
N H
(\ 2HCI
Compound 23A
5 Synthesis of compound 23A
Compound 23A was prepared via the coupling of methanesulfonic acid 1-methyl-
piperidin-2-
ylmethyl ester HCI with ethyl 4-methyl-1 H-imidazole-5-carboxylate using KOH
as the base
in DMSO at 60 C for 40 hours, subsequent separation of the formed
regioisomers by flash
chromatography (dichloromethane/methanol = 95/5 (v/v)), followed by conversion
of the
10 resulting ester to the corresponding carboxylic acid (lithium
hydroxide/THF/water; at 60 C
for 20 hours) and coupling of the formed carboxylic acid with (-)-cis-
myrtanylamine using
PyBOP (benzotriazol-l-yloxytris(pyrrolidino)-phosphonium hexafluorophosphate)
as the
coupling reagent in the presence of diisopropylethylamine in dichloromethane.
The crude
compound 23A was further purified by flash chromatography
(dichloromethane/methanol =
15 95/5 (v/v)), followed by conversion of the isolated free base to the
dihydrochloride salt.
Compound 23A. Melting point: 148-153 C.
Synthesis of compound 24
Part A: To a magnetically stirred solution of ethyl N-benzyl-5-methyl-1 H-
imidazole-4-
20 carboxylate (8.4 gram, 0.0345 mol) in methanol (200 ml) was slowly added a
solution of
KOH (7.3 gram, 85 % grade, 0.110 mol) and the resulting mixture was heated at
80 C for 2
hours. The solution was cooled to room temperature and concentrated HCI (9.2
ml) was
subsequently added. The formed precipitate was collected by filtration to give
N-benzyl-5-
methyl-1 H-imidazole-4-carboxylic acid (6.77 gram, 91 % yield). Melting point:
292 C
25 (decomposition).
Part B: To a magnetically stirred solution of N-benzyl-5-methyl-1 H-imidazole-
4-carboxylic
acid (6.77 gram, 0.031 mol) in anhydrous acetonitrile (35 ml) was successively
added
diisopropylethylamine (DIPEA) (17.2 ml, 0.0992 mol), HBTU (14.098 gram, 0.0372
mol) and
methoxy-methylamine (3.63 gram, 0.0372 mol). The resulting mixture was reacted
at 20 C
30 for 16 hours and subsequently concentrated in vacuo. The resulting residue
was taken up in
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ethylacetate and successively washed with 5 % aqueous NaHCO3 solution and
water. The
organic layer was dried over MgSO4, filtered and concentrated in vacuo. The
resulting oily
residue (18.45 gram) was purified by flash chromatography (ethyl
acetate/acetone = 7/3
(v/v)) to give N-methoxy-N-methyl-5-methyl-l-benzyl-lH-imidazole-4-carboxamide
(10.77
gram, 82 % yield). MH+ = 260. 'H-NMR (400 MHz, CDCI3): b 2.34 (s, 3H), 3.47
(s, 3H), 3.77
(s, 3H), 5.09 (s, 2H), 7.05-7.10 (m, 2H), 7.18-7.28 (m, 3H), 7.48 (s, 1 H).
Part C: To a magnetically stirred solution of 1-naphtylmagnesium bromide (49
ml, 0.25 M in
THF, 0.00123 mol) was added a solution of N-methoxy-N-methyl-5-methyl-l-benzyl-
1H-
imidazole-4-carboxamide (2.69 gram, 0.0104 mol) in anhydrous THF (10 ml) and
the
resulting solution was stirred for 1 hour. The reaction mixture was quenched
in 1 N HCI (21
ml) and subsequently extracted with ethyl acetate (EtOAc). The EtOAc layer was
twice
washed with water, dried over MgSO4, filtered and concentrated in vacuo. The
resulting
crude residue was purified by flash chromatography (ethyl acetate/petroleum
ether = 1/1
(v/v)), followed by another flash chromatographic purification
(dichloromethane/methanol =
99/1 (v/v)) to give pure compound 24 (1.35 gram, 66 % yield) as an oil. 'H-NMR
(400 MHz,
CDCI3): b 2.58 (s, 3H), 5.12 (s, 2H), 7.08-7.13 (m, 2H), 7.31-7.40 (m, 3H),
7.44-7.56 (m, 4H),
7.78-7.82 (m, 1 H), 7.84-7.89 (m, 1 H), 7.92-7.96 (m, 1 H), 8.16-8.22 (m, 1
H).
0
N
N
Compound 24
Synthesis of compound 25
Analogously was prepared compound 25 (from N-methoxy-N-methyl-5-methyl-1 -
phenyl-1 H-
imidazole-4-carboxamide and n-hexyllithium in anhydrous diethyl ether). Flash
chromatographic purification (methyl-tert-butyl ether/petroleum ether = 1/3
(v/v)) of the
initially isolated crude product gave compound 25 (24 % yield) as a pale
yellow oil.
0
NII
N
Compound 25
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Compound 25. 'H-NMR (400 MHz, CDCI3): b 0.86-0.94 (m, 3H), 1.25-1.47 (m, 6H),
1.70-
1.80 (m, 2H), 2.50 (s, 3H), 3.04-3.11 (m, 2H), 7.26-7.32 (m, 2H), 7.50-7.59
(m, 4H).
Analogously was prepared compound 26
0
jlNl
6
Compound 26
Compound 26; Rf (methanol/dichloromethane = 3/97 (v/v), silica gel) = 0.65.
Synthesis of compound 27
To a magnetically stirred solution of N-(adamant-1-yl)-1-phenyl-lH-imidazole-4-
carboxylate
(1.61 gram, 0.005 mol) in dichloromethane (20 ml) was added a solution of Br2
(0.52 ml,
0.010 mmol) in dichloromethane (5 ml). The resulting mixture was reacted at
room
temperature for 4 hours. Dichloromethane and 5 % aqueous NaHCO3 solution was
added to
the reaction mixture. The separated organic layer was dried over MgS04,
filtered and
concentrated in vacuo. The resulting residue was purified by flash
chromatography
(dichloromethane/acetone = 19/1 (v/v)). Subsequent recrystallisation from
acetonitrile gave
N-(adamant-1-yl)-5-bromo-l-phenyl-lH-imidazole-4-carboxamide (0.51 gram, 26 %
yield).
Melting point: 229-232 C.
0
N~N~
~
N Br
6
Compound 27
Analogously was prepared compound 28 in 17 % yield using N-chlorosuccinimide
(NCS) as
the chlorinating agent for 40 hours at room temperature. Flash chromatography
(dichloromethane/acetone = 19/1 (v/v)). Melting point: 209-213 C.
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0
NN~
~ H ~~
N CI
b
Compound 28
Synthesis of compound 29
To a magnetically stirred solution of N-(adamant-1-yl)-5-bromo-1-phenyl-1H-
imidazole-4-
carboxylate (0.60 gram) in dichloromethane (20 ml) was added a solution of Br2
(0.30 ml) in
dichloromethane (5 ml) and triethylamine (0.21 ml). The resulting mixture was
reacted at
room temperature for 50 hours. Dichloromethane and 5 % aqueous NaHCO3 solution
was
added to the reaction mixture. The separated organic layer was dried over
MgS04, filtered
and concentrated in vacuo. The resulting residue was purified by flash
chromatography
(dichloromethane). Subsequent stirring in diethyl ether followed by filtration
gave N-
(adamant-l-yl)-2,5-dibromo-1-phenyl-1H-imidazole-4-carboxamide (0.29 gram).
Melting
point: 228-231 C.
0
N N
H
BrN Br
b
Compound 29
Analogously was prepared compound 30 in 32 % yield from N-(adamant-1-yl)-5-
chloro-1-
phenyl-1 H-imidazole-4-carboxylate using N-chlorosuccinimide (NCS) as the
chlorinating
agent. Melting point: 193-195 C.
0
N~-H~
CIN G
b
Compound 30
Synthesis of compound 31
To a magnetically stirred suspension of N-(adamant-1-yl)-2-methyl-1-phenyl-1H-
imidazole-4-
carboxylate (2.01 gram, 0.006 mol) in anhydrous THF (20 ml) under N2 at -70 C
was slowly
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added a solution of lithium diisopropylamide (LDA) (9.0 ml of a 2 M solution
in heptane/THF,
0.018 mol LDA) under N2 at -70 C and the resulting solution was stirred for 1
hour. A
solution of para-tolyisulfonyl cyanide (1.63 gram, 0.009 mol) in anhydrous THF
(10 ml) was
added and the resulting solution was stirred for 1 hour at -70 C. The
solution was allowed to
attain room temperature and stirred for another 12 hours and subsequently
quenched with
water. The mixture was extracted with diethyl ether. The organic layer is
dried over MgSO4,
filtered and concentrated in vacuo. The resulting residue was purified by
flash
chromatography (dichloromethane/acetone = 19/1 (v/v)) and subsequently
recrystallized
from acetonitrile to give compound 31 (0.23 gram, 11 % yield). Melting point
compound 30:
246-248 C.
0
~N
~ H //
N CN
6
Compound 31
Analogously was prepared compound 32 in 31 % yield from N-(adamant-1-yl)-2-
methyl-1-
phenyl-1 H-imidazole-4-carboxylate using dimethyidisulfide (CH3SSCH3). Melting
point: 172-
173 C.
0
N~ N
~
H ~/~
N SCH3
b
Compound 32
Analogously was prepared compound 33 in 28 % yield from N-(adamant-1-yl)-2-
methyl-1-
phenyl-1 H-imidazole-4-carboxylate using para-tolyisulfonyl chloride. Melting
point: 216-218
C.
0
N
~
II H T~j
N CI
b
Compound 33
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Analogously was prepared compound 33A from N-(adamant-1-yl)-2-methyl-l-phenyl-
1H-
imidazole-4-carboxylate using para-tolyisulfonyl bromide. Melting point: 242-
244 C.
0
N~
II H
N Br
6
Compound 33A
5 Analogously was prepared compound 34 in 7 % yield from N-(adamant-1-yl)-1-
phenyl-1H-
imidazole-4-carboxylate using para-tolyisulfonyl cyanide. Melting point: 237-
239 C.
0
N H ~
N
CN~N CN
b
Compound 34
Analogously was prepared compound 35 in 12 % yield from N-(adamant-1-yl)-1-
phenyl-1H-
10 imidazole-4-carboxylate using dimethyidisulfide (CH3SSCH3). Melting point:
166-168 C.
0
H
N N
H3CS~N
6
Compound 35
General: Compounds 36 - 114 were all prepared according to the general method
outlined
in Scheme 3 hereinabove. The obtained compounds of general formula (IV) were
converted
15 (see Scheme 1 hereinabove) via the corresponding carboxylic acids of
general structure (V)
to the compounds of general formula (I) wherein X represents subgroup (ii)
Synthesis of compound 36
Part A: NaNO2 (13.8 gram) was dissolved in water (48 ml) at 4 C. The resulting
solution
was slowly added to a magnetically stirred solution of 3-oxo-butyric acid
methyl ester (17.4
20 gram, 0.15 mol) while keeping the temperature < 5 C. After stirring the
mixture for two hours
water (120 ml) was added and the resulting mixture was extracted twice with
diethyl ether.
The combined organic layers were successively washed with water and a 5 %
aqueous
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NaHCO3 solution. The organic layer was dried over MgSO4, filtered and
thoroughly
concentrated to give crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24
gram) as a
colorless oil which was not further purified. 'H-NMR (400 MHz, CDCI3): b 2.42
(s, 3H), 3.91
(s, 3H), 9.90 (br s, 1 H).
Part B: Crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram, - 0.15
mol)
dissolved in a magnetically stirred mixture of acetic acid (293 ml), acetic
acid anhydride (110
ml) and Pd/C (4 gram) was hydrogenated for 20 hours at room temperature at 1
atmosphere
H2 pressure. After filtration over hyflo, the acetic acid and acetic acid
anhydride were
removed by concentration in vacuo. The resulting crude mixture was purified by
flash
chromatography (dichloromethane/methanol = 95/5 (v/v)) to give 2-acetylamino-3-
oxo-
butyric acid methyl ester (16.7 gram, 60 % yield) as a white solid. Rf
(dichloromethane/methanol = 95/5 (v/v)) = 0.4. 'H-NMR (400 MHz, CDCI3): b 2.08
(s, 3H),
2.40 (s, 3H), 3.83 (s, 3H), 5.29 (d, J - 7, 1 H), 6.71 (br s, 1 H).
Part C: To a magnetically stirred solution of 2-acetylamino-3-oxo-butyric acid
methyl ester (5
gram, 28.9 mmol) in butyronitrile was added aniline (3.42 ml) and
trifluoroacetic acid (2.89
ml) and the resulting mixture was heated at reflux for 45 minutes. The
butyronitrile was
removed in vacuo at room temperature and the resulting residues was taken up
dichloromethane and washed twice with an aqueous potassium carbonate solution.
The
organic layer was dried over MgSO4, filtered and concentrated in vacuo. The
resulting
residue was purified by flash chromatography (diethyl ether/acetone = 4/1
(v/v)) to give
methyl 2,5-dimethyl-l-phenyl-1H-imidazole-4-carboxylate (3.0 gram, 46 %
yield). 'H-NMR
(400 MHz, CDCI3): b 2.22 (s, 3H), 2.33 (s, 3H), 3.91 (s, 3H), 7.18-7.22 (m,
2H), 7.51-7.59 (m,
3H).
Part D: To a magnetically stirred solution of methyl 2,5-dimethyl-l-phenyl-1H-
imidazole-4-
carboxylate (8.0 gram, 0.035 mol) in THF (100 ml) was added a solution of LiOH
(1.68 gram)
in water (100 ml). The resulting mixture was heated at 70 C for 16 hours,
allowed to attain
room temperature and acidified with 2 molar equivalents of a 1 N HCI solution.
The formed
precipitate was collected to give crude 2,5-dimethyl-1 -phenyl-1 H-imidazole-4-
carboxylic acid
(7.0 gram, 93 % yield). 'H-NMR (400 MHz, DMSO-d6): b 2.31 (s, 3H), 2.43 (s,
3H), 7.56-7.61
(m, 2H), 7.66-7.71 (m, 3H).
Part D: To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1 H-
imidazole-4-carboxylic
acid (0.6 gram, 0.0028 mol) in acetonitrile (35 ml) was successively added
diisopropylethylamine (DIPEA, Hunig's base) (1.27 gram), O-benzotriazol-1-yl-
N, N, N', N'-
tetramethyluronium hexafluorophosphate (HBTU) (1.27 gram) and (-)-cis-
myrtanylamine
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(1.05 ml, 0.0028 mol). The resulting mixture was reacted at 20 C for 16 hours
and
subsequently concentrated in vacuo. The resulting residue was taken up in
dichloromethane
and washed with 5 % aqueous NaHCO3 solution. The organic layer was dried over
MgSO4,
filtered and concentrated in vacuo. The resulting residue was purified by
flash
chromatography (dichoromethane/methanol = 95/5 (v/v)) to give N-[(1 R,2S,5R)-
rel-6,6-
dimethylbicyclo[3.1.1]heptan-2-methyl]-2,5-dimethyl-l-phenyl-1 H-imidazole-4-
carboxamide
(compound 36) (0.70 gram, 72 % yield). Rf (silica gel/ dichoromethane/methanol
= 95/5 (v/v))
-0.6.
0
H H N
H
Compound 36
Analogously were prepared compounds 37 -47:
0
N \ ~
~j~ H
~N \ / \
Compound 37
Compound 37:1H-NMR (400 MHz, CDCI3): b 1.26 (t, J 7, 3H), 2.41 (s, 3H), 2.56
(q, J 7,
2H), 7.23-7.28 (m, 2H), 7.49-7.60 (m, 6H), 7.66 (d, J 8, 1 H), 7.88 (d, J 8, 1
H), 8.11 (d, J
= 8, 1 H), 8.28 (d, J 8, 1 H), 9.85 (s, 1 H).
0
N \ ~
~ ~ H
N \ /
.HCI
Compound 38
Compound 38: Melting point: 177-179 C.
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0
N~H,
N
b
Compound 39
Compound 39: from endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine.
Melting point:
130-132 C (DSC).
0
N H,
~N
I
Compound 40
Compound 40: from endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine.
'H-NMR (300 MHz, CDCI3): b 0.89 (s, 3H), 0.96 (t, J = 7, 3H), 1.12 (s, 3H),
1.17-1.27 (m,
5H), 1.40-1.60 (m, 2H), 1.67-1.81 (m, 3H), 2.15 (s, 3H), 2.70-2.95 (m, 2H),
3.78 (dd, J -10
and 2, 1 H), 7.18-7.23 (m, 2H), 7.34 (br d, J - 10, 1 H), 7.48-7.57 (m, 3H).
0
N
'
N
\ I F
Compound 41
Compound 41: Melting point: 117.5-120 C (DSC).
0
H CI
N
I
Compound 42
Compound 42: Melting point: 193-196 C (DSC).
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0
JH
N CFs
i I
~
Compound 43
Compound 43: Melting point: 157-159 C (DSC).
0
NII H CF3
-I
N \ / \
Compound 44
Compound 44: Melting point: 76-79 C (DSC).
0
N
N Compound 45
Compound 45: From R-(+)-phenethylamine.
'H-NMR (300 MHz, CDCI3): b 1.58-1.61 (m, 3H), 2.17 (s, 3H), 2.33 (s, 3H), 5.25-
5.35 (m,
1 H), 7.15-7.54 (m, 11 H).
0
N
J
N N \
Compound 46
Compound 46: Melting point: 139-141 C (DSC).
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O
H O+
-
N Compound 47
Compound 47: 'H-NMR (400 MHz, CDCI3): b 1.10 (s, 9H), 1.69 (s, 3H), 2.24 (s,
3H), 7.00-
7.06 (m, 2H), 7.46-7.55 (m, 3H), the NH peak is invisible and probably merged
with the H20
peak at b 1.60.
5
Synthesis of compound 48
To a magnetically stirred solution of 2,5-dimethyl-l-phenyl-1H-imidazole-4-
carboxylic acid
(0.66 gram, 0.00306 mol) in dichloromethane (35 ml) was successively added
diisopropylethylamine (DIPEA) (3.1 ml), CIP (2-chloro-1,3-
dimethylimidazolinium
10 hexafluorophosphate) (2.55 gram) and 3-hydroxyadamantane amine (0.612 gram,
0.00366
mol). The resulting mixture was reacted at 20 C for 16 hours and subsequently
concentrated in vacuo. The resulting residue was taken up in dichloromethane
and washed
with 5 % aqueous NaHCO3 solution. The organic layer was dried over MgS04,
filtered and
concentrated in vacuo. The resulting residue was purified by flash
chromatography
15 (dichoromethane/methanol = 98/2 (v/v)) to give N-(3-hydroxyadamant-1-yl)-
2,5-dimethyl-l-
phenyl-1 H-imidazole-4-carboxamide (0.75 gram, 67 % yield). Rf (silica gel/
dichoromethane/methanol = 98/2 (v/v)) - 0.6. Melting point: 215-220 C.
O
N
N I H
'N
I ~ OH
Compound 48
20 Analogously were prepared compounds 49-85:
o ~
N~N
H
Compound 49
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Compound 49: Melting point: 245-247 C.
O
~ H
N /
i I
\
Compound 50
Compound 50: Melting point: 251-253 C.
O
H .~ N
racemic,endo
Compound 51
Compound 51: (from racemic endo-2-amino-bicyclo[2.2.1]heptane: 'H-NMR (400
MHz,
DMSO-d6): b 0.85-1.64 (m, 8H), 2.13 (s, 3H), 2.21 (br s, 1 H), 2.24 (s, 3H),
2.40 (br s, 1 H),
4.07-4.16 (m, 1 H), 7.34 (br d, J - 8, 2H), 7.40 (br d, J - 7, 1 H), 7.52-7.61
(m, 3H).
0
H-,~)
N
A
N
/
\
Compound 52
Compound 52: (from noradamantylamine): Melting point: 147-150 C.
O H FL
NJF
N F
/I N
Compound 53
Compound 53: Melting point: 111-113 C.
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N~N
0
-13
II H
Compound 54
Compound 54: Melting point: 204-207 C.
0
N NII~/ G
I
Compound 55
Compound 55: Melting point: 115-117 C.
0
N~N
II H
N
0
F
Compound 56
Compound 56: Melting point: 208-210 C.
0
N
N 0
Ci Compound 57
Compound 57: Melting point: 243-245 C.
0
N
N \ /
I N~
NS
0
F Compound 58
Compound 58: Melting point: 178-181 C.
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0
11 N \ /
H \ 'N
i I CF3
\
\
Compound 59
Compound 59: 1H-NMR (300 MHz, CDCI3): b 2.28 (s, 3H), 2.43 (s, 3H), 7.23-7.27
(m, 2H),
7.55-7.60 (m, 3H), 7.79 (dd, J = 9 and 2 Hz, 1 H), 8.22 (d, J = 9 Hz, 1 H),
8.42 (s, 1 H), 8.62
(d, J - 5 Hz, 1 H), 8.94 (d, J = 5 Hz, 1 H), 10.25 (br s, 1 H).
Melting point: 198.5 C (DSC).
0
H CN
~ I
N
I
Compound 60
Compound 60: 1H-NMR (300 MHz, CDCI3): b 2.29 (s, 3H), 2.43 (s, 3H), 7.23-7.27
(m, 2H),
7.54-7.60 (m, 3H), 7.70-7.76 (m, 2H), 7.95 (d, J 8 Hz, 1 H), 8.17-8.21 (m, 1
H), 8.27-8.29
(m, 1 H), 8.63 (d, J= 8 Hz, 1 H), 10.20 (br s, 1 H).
Melting point: 241.5 C (DSC).
0
N H
Compound 61
Compound 61: Melting point: 171-172 C.
0
H
~N 0-
Compound 62
Compound 62: Melting point: -113 C. Rf (diethyl ether/petroleum ether = 1/1
(v/v) - 0.15.
1H-NMR (400 MHz, CDCI3): b 1.66-1.78 (m, 6H), 2.08-2.18 (m, 9H), 2.19 (s, 3H),
3.22 (s,
3H), 4.59 (s, 3H), 7.06 (br s, 1 H), 7.25-7.30 (m, 2H), 7.47-7.55 (m, 3H).
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0
N
H
HCI
0-0
o--~ Compound 63
Compound 63: Melting point: 221-223 C.
0
1
I H
F~ N
F N
F
Compound 64
Compound 64: Melting point: 170-172 C.
0
N IF H
F
~ I F
Compound 65
Compound 65: Melting point: 168-170 C.
0I
N~ H
F
F_~/\N
F
Compound 66
Compound 66: (from endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine).
Melting point:
102-107 C.
0
N H
N
I ~
HCI
Compound 67
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Compound 67: Melting point: 166-168 C.
0
N
N
H
N
6
Compound 68
Compound 68: Melting point: 208-210 C.
5
0
~H
N CI CI
a
Compound 69
Compound 69: Melting point: 154-156 C.
0
H
~
N
I
racemic,endo
Compound 70
10 Compound 70: (from racemic endo-2-amino-bicyclo[2.2.1]heptane.
Melting point: 165-167 C.
0
N H
N~
NIk S
~-
Compound 71
Compound 71: Melting point: 69-72 C.
0II
H
N
NIk S
~-
Compound 72
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Compound 72:1H-NMR (400 MHz, CDCI3): b 1.66-1.78 (m, 6H), 2.08-2.17 (m, 9H),
2.32 (s,
3H), 2.51 (s, 3H), 6.95 (br s, 1 H), 7.51 (d, J = 4, 1 H), 7.83 (d, J = 4, 1
H). Melting point: 130-
133 C.
0II
N~ H
N II~
0
cl
Compound 73
Compound 73: (from endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine).
Melting point:
146-148 C.
0
ii-H
0-
Compound 74
Compound 74: 'H-NMR (400 MHz, CDCI3): b 1.65-1.78 (m, 6H), 2.08-2.19 (m, 12H),
2.27 (s,
3H), 3.78 (s, 3H), 6.97 (br s, 1 H), 7.03-7.12 (m, 3H), 7.43-7.49 (m, 1 H).
0
H
N~
0-
Compound 75
Compound 75: 'H-NMR (400 MHz, CDCI3): b 2.21 (s, 3H), 2.37 (s, 3H), 3.82 (s,
3H), 7.07-
7.13 (m, 2H), 7.16-7.21 (m, 1 H), 7.46-7.59 (m, 4H), 7.66 (d, J = 8, 1 H),
7.87 (d, J = 8, 1 H),
8.13 (d, J = 8, 1 H), 8.28 (d, J = 8, 1 H), 9.70 (br s, 1 H).
0
H~
NII~ \~~///
N- .fumaric acid
Compound 76
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Compound 76: Melting point: 217-219 C.
0
I H
N~
N I
F
Compound 77
Compound 77: Melting point: 217-218 C. In the synthesis of this particular
compound 2-
Chloro-1,3-dimethylimidazolinium chloride was used in the last reaction step
as the coupling
reagent instead of CIP.
OH
NII N
NI / ~
b 0
Compound 78
Compound 78: Melting point: 186-187 C. In the synthesis of this particular
compound 2-
Chloro-1,3-dimethylimidazolinium chloride was used in the last reaction step
as the coupling
reagent instead of CIP.
0
H
N
N
Compound 79
Compound 79: Melting point: 123-125 C.
0
N
~ I H
N 0
/~
\
\
Compound 80
Compound 80: Melting point: 214-217 C.
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0
N F F
\~ H / \ F
N
i I
~
Compound 81
Compound 81: Melting point: 149-150 C.
0
N
N ~
H
N
6
Compound 82
Compound 82: 'H-NMR (400 MHz, CDCI3): b 0.75-0.80 (m, 2H), 0.97-1.03 (m, 2H),
1.45-
1.52 (m, 1 H), 1.65-1.78 (m, 6H), 2.08-2.18 (m, 9H), 2.34 (s, 3H), 6.98 (br s,
1 H), 7.23-7.28
(m, 2H), 7.45-7.56 (m, 3H). In the synthesis of this particular compound 2-
chloro-1,3-
dimethylimidazolinium chloride was used in the last reaction step as the
coupling reagent
instead of CIP.
O H F F
N~N F
N
6
Compound 83
Compound 83: 'H-NMR (400 MHz, CDCI3): b 0.75-0.80 (m, 2H), 0.97-1.02 (m, 2H),
1.45-
1.52 (m, 1 H), 2.38 (s, 3H), 4.80 (br d, J = 7, 2H), 7.25-7.30 (m, 2H), 7.35
(br t, J = 7, 1 H),
7.47-7.68 (m, 7H).
0
N'Y
N
N Compound 84
Compound 84: Melting point: 136-137 C.
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0
N ~
~N
N
I
Compound 85
Compound 85: Rf (dichloromethane / methanol = 97/3 (v/v)) = 0.2.
0
jjJH
N
fumaric acid
exo, racemic
Compound 86
Compound 86: Melting point: 242-244 C. MH+ (free base) = 368. Compound 86 was
derived
from racemic exo-2-aminobicyclo[2.2.1]heptane and 2-acetylamino-3-oxo-butyric
acid methyl
ester analogously to the synthesis as described herein above for compound 36 ,
part C.
0
jj~H
~<N~
~~H
Compound 87
Compound 87: Melting point: 181-183 C. MH+ = 410. Compound 87 was derived
from (-)-
cis-myrtanylamine (CAS 38235-68-6) and 2-acetylamino-3-oxo-butyric acid methyl
ester
analogously to the synthesis as described herein above for compound 36, part
C.
0
Il H
/~N~~ \/~
pJ
Compound 88
Compound 88: Rf (dichloromethane / methanol = 97/3 (v/v)) = 0.2. In the
synthesis of this
particular compound 2-chloro-1,3-dimethylimidazolinium chloride was used in
the last
reaction step as the coupling reagent instead of CIP.
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Synthesis of compound 89
Part A: To a magnetically stirred suspension of 2,5-dimethyl-l-phenyl-1H-
imidazole-4-
carboxylic acid (0.4 gram, 1.85 mmol) in CHCI3 (4 ml) was added oxalyl
chloride (0.34 gram,
2.685 mmol) and the resulting mixture was reacted at 58 C for 2 hours and
subsequently
5 concentrated in vacuo. The resulting residue was taken up in dichloromethane
and
diisopropylethylamine (0.28 gram, 2.148 mmol) was subsequently added. A
solution of 2,3-
dichloroaniline (0.35 gram, 2.146 mmol) in dichloromethane (5 ml) was slowly
added to the
resulting mixture and the resulting mixture was reacted for 2 hours at room
temperature and
subsequently concentrated in vacuo. The resulting residue was purified by
flash
10 chromatography (dichloromethane) to give N-(2,3-dichlorophenyl)-2,5-
dimethyl-1 -phenyl-1 H-
imidazole-4-carboxamide (compound 89) (0.24 gram, 36 % yield). Melting point:
127-129 C.
0 Ci. CI
N N~
Compound 89
15 Analogously were prepared compounds 90-114:
o N-0
~ N
6 /
\
Compound 90
Compound 90: 'H-NMR (400 MHz, CDCI3): b 1.50-1.78 (m, 12H), 1.88-1.98 (m, 2H),
2.18 (s,
3H), 2.34 (s, 3H), 4.12-4.23 (m, 1 H), 7.10-7.20 (m, 3H), 7.48-7.57 (m, 3H).
20 LC/MS: retention time: 2.88 minutes; MH+ = 326.
o OH
N
H
N
i
\
Compound 91
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Compound 91: 'H-NMR (400 MHz, CDCI3): b 1.65-2.07 (m, 9H), 2.17 (s, 3H), 2.32
(s, 3H),
3.73 (s, 2H), 7.16-7.20 (m, 2H), 7.41 (br s, 1 H), 7.49-7.57 (m, 3H).
LC/MS: retention time: 2.22 minutes; MH+ = 314.
0
N
N
b
Compound 92
Compound 92: 'H-NMR (400 MHz, CDCI3): b 1.56-1.66 (m, 4H), 1.73-1.87 (m, 4H),
2.18 (br
s, 6H), 3.65 (t, J = 7, 2H), 3.91 (t, J = 7, 2H), 7.19-7.23 (m, 2H), 7.47-7.56
(m, 3H).
LC/MS: retention time: 2.12 minutes; MH+ = 297.
0
H
/k N
N
6 .fumaric acid
Compound 93
Compound 93: Rf (dichloromethane/methanol = 95/5 (v/v)) = 0.65.
0
N
~ H ~,N
N
b
Compound 94
Compound 94: LC/MS: retention time: 1.88 minutes; MH+ = 307.
0
H
N
6 Compound 95
Compound 95: Melting point: 134-135 C.
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0II
N F
NIN H
F
F
Compound 96
Compound 96: Melting point: 119-121 C.
0
N
N H~
Sumaric acid
Compound 97
Compound 97: Rf (dichloromethane/methanol = 97/3 (v/v)) = 0.6.
0
NI,I H
NI
Compound 98
Compound 98: Melting point: 125-127 C.
0
N / ~
N~
Compound 99
Compound 99: 'H-NMR (400 MHz, CDCI3): b 1.60 (d, J 7, 3H), 2.17 (s, 3H), 2.33
(s, 3H),
5.30 (quintet, J = 7, 1 H), 7.15-7.54 (m, 11 H).
LC/MS: retention time: 2.60 minutes; MH+ = 320.
o
H
J
N
/I
\
Compound 100
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Compound 100: 'H-NMR (400 MHz, CDCI3): b 2.15 (s, 3H), 2.36 (s, 3H), 2.97 (dd,
J - 15
and 6, 2H), 3.40 (dd, J - 15 and 8, 2H), 4.88-4.98 (m, 1 H), 7.16-7.27 (m,
6H), 7.37 (br d, J -
8, 1 H), 7.48-7.57 (m, 3H).
LC/MS: retention time: 2.63 minutes; MH+ = 332.
o
N
"
N
6 Compound 101
Compound 101: 'H-NMR (400 MHz, CDCI3): b 2.18 (s, 3H), 2.34 (s, 3H), 6.44 (d,
J 8, 1 H),
7.15-7.38 (m, 12H), 7.48-7.57 (m, 3H), 7.92 (br d, J - 8, 1 H).
LC/MS: retention time: 3.59 minutes; MH+ = 382.
0
N
N
/
Compound 102
Compound 102: LC/MS: retention time: 1.30 minutes; MH+ = 338.
o
N
H
~ N
/
~ Compound 103
Compound 103: LC/MS: retention time: 2.81 minutes; MH+ = 356.
o
H
III N
N
Compound 104
Compound 104: LC/MS: retention time: 2.98 minutes; MH+ = 396.
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0
II N~ [p~
~ V
N
i
\
Compound 105
Compound 105: LC/MS: retention time: 2.17 minutes; MH+ = 300.
p
N N ~ I
jj
H H
N
/
\
Compound 106
Compound 106: LC/MS: retention time: 2.08 minutes; MH+ = 346.
0
N
H ~
N
a
Compound 107
Compound 107: Melting point: 117-118 C.
0
N H
~~I\N
6
Compound 108
Compound 108: Melting point: 123-125 C.
0
U-H x ~
I~~//I
i
~ I
Compound 109
Compound 109: Melting point: 130-132 C.
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O
ZN O-
H ~ ~
N ~ O'
/~
Compound 110
Compound 110: 'H-NMR (400 MHz, CDCI3): b 2.17 (s, 3H), 2.37 (s, 3H), 3.86 (s,
3H), 3.88
(s, 3H), 4.55 (d, J - 6, 2H), 6.82 (d, J = 8, 1 H), 6.90-6.95 (m, 2H), 7.17-
7.21 (m, 2H), 7.45 (br
s, 1 H), 7.50-7.57 (m, 3H).
5
O
jj H
N
Compound 111
Compound 111: Rf (dichloromethane / methanol = 95/5 (v/v)) = 0.65.
O
H
~~
N
/
Compound 112
10 Compound 112: 'H-NMR (400 MHz, CDCI3): b 2.16 (s, 3H), 2.35 (s, 3H), 2.93
(t, J 7, 2H),
3.66 (q, J - 7, 2H), 7.16-7.34 (m, 8H), 7.48-7.56 (m, 3H).
LC/MS: retention time: 3.13 minutes; MH+ = 320.
O
N
N Y-X
~
Compound 113
15 Compound 113: LC/MS: retention time: 2.67 minutes; MH+ = 352.
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0
-til ~'H
N
i I
~
Compound 114
Compound 114: 'H-NMR (400 MHz, CDCI3): b 0.94-1.05 (m, 2H), 1.11-1.31 (m, 3H),
1.52-
1.87 (m, 6H), 2.18 (s, 3H), 2.35 (s, 3H), 3.25 (t, J = 7, 2H), 7.16-7.21 (m,
2H), 7.22-7.29 (m,
1 H), 7.48-7.57 (m, 3H).
LC/MS: retention time: 2.76 minutes; MH+ = 312.
EXAMPLE 3: FORMULATION OF COMPOUND 1
For oral (p.o.) administration: To the desired quantity (0.5-5 mg) of the
solid compound 1
in a glass tube, some glass beads were added and the solid was milled by
vortexing for 2
minutes. After addition of 1 ml of a solution of 1% methylcellulose in water
and 2% (v/v) of
Poloxamer 188 (Lutrol F68), the compound was suspended by vortexing for 10
minutes. The
pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). Remaining
particles in the
suspension were further suspended by using an ultrasonic bath.
For intraperitoneal (i.p.) administration: To the desired quantity (0.5-15 mg)
of the solid
compound 1 in a glass tube, some glass beads were added and the solid was
milled by
vortexing for 2 minutes. After addition of 1 ml of a solution of 1%
methylcellulose and 5%
mannitol in water, the compound was suspended by vortexing for 10 minutes.
Finally the pH
was adjusted to 7.
EXAMPLE 4: PHARMACOLOGICAL TEST RESULTS
Cannabinoid receptor affinity data obtained according to the protocols given
above are
shown in the table below. BMS-1, BMS-II and BMS-III are the three exemplified
imidazoles
in WO 01/58869 (examples 64, 65 and 66 therein, respectively). These three
specific
imidazole derivatives all contain a L-phenylalanine derived carboxamide moiety
at the 4-
position of their (1 H)-imidazole moiety as shown below. Our invention
includes novel 1 H-
imidazole derivatives which lack such a L-phenylalanine derived carboxamide
moiety but
have approximately hundred-fold higher CB2 receptor affinities as compared to
the prior art
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compounds exemplified in WO 01/58869 as becomes clear from the data depicted
in Table
1.
N N 0
0
N O
~ N ~\ //
-~0 /N ~ H ~ H O N 'N ~ ~
O ~ H O O
OJr O o r, N -~
BMS-I BMS-I I BMS-II I
Table 1
Human cannabinoid-CB, Human cannabinoid-CB2
receptor receptor
Compound In vitro affinity - pKl In vitro affinity - pKlvalue
BMS-1 - 6.4
BMS-11 - < 6.0
BMS-III - 7.2
Compound 1 < 6.0 7.3
Compound 11 < 6.0 9.0
Compound 14 < 6.0 8.2
Compound 15 6.2 > 9.0
Compound 20 6.6 8.0
Compound 26 - 6.8
Compound 33 - 8.1
Compound 33A 6.1 8.2
Compound 44 - 8.8
Compound 49 < 6.0 8.6
Compound 90 - 8.3
- = not determined
