Note: Descriptions are shown in the official language in which they were submitted.
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1,2-DIARYL BENZIMIDAZOLES FOR TREATING ILLNESSES ASSOCIATED
WITH A MICROGLIA ACTIVATION
The invention relates to new benzimidazole derivatives and
the use of benzimidazole derivatives for the production of
pharmaceutical agents for treatment and prophylaxis of diseases
that are associated with a microglia activation.
Almost all degenerative diseases of the central nervous
system are connected to chronic inflammation. A central step of
the inflammation process is the activation of mononuclear
phagocyte cells, the microglia. This is carried out in, e.g.,
Alzheimer's disease by senile plaques, in Creutzfeldt-Jakob
disease by a prion protein and in ischemic stroke by dead cells.
The microglia can remain for a prolonged period in the activated
.state, in which they produce and secrete various inflammation
factors, e.g., reactive oxygen/nitrogen intermediate products,
proteases, cytokines, complement factors and neurotoxins. The
latter in turn produce neuronal dysfunction and degeneration.
For a possible treatment of neuroinflammation, to date non-
steroidal antiinflammatory agents (COX II inhibitors) (McGeer, P.
L.; Roger, Neurology 42, 447-449 (1992), Rogers, J.; Kirby, L.
C.; Hempleman, S. R.; Berry, D. L.; McGeer, P. L.; Kaszniak, A.
W.; Zalinski, J.; Cofield, M.; Mansukhani, L.; Wilson, P.; Kogan,
F. Neurology 43, 1609-1611 (1993), Andersen, K.; Launer, L. J.;
Ott, A.; Hoes, A. W.; Breteler, M. M. B.; Hofman, A. Neurology
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45, 1441-1445 (1995), Breitner, J. C. S.; Gau, B. A.; Welsh, K.
A.; Plassman, B. L.; McDonald, W. M.; Helms, M. J.; Anthony, J.
C. Neurology 44, 227-232 (1994), The Canadian Study of Health and
Aging, Neurology 44, 2073-2079 (1994)), cytokine modulators
(McGeer, P. L.; McGeer, E. G. Brain Res. Rev 21:195-218 (1995),
McGeer, E. G.; McGeer, P. L., CNS Drugs 7, 214-228 (1997),
Barone, F. C. and Feuerstein, G. Z., J. Cerebral Blood Flow and
Metabolism 19, 819-834 (1999) and complement-cascade-inhibitors
(Chen., S.; Frederickson, R. C. A., and Brunden, K. R.,
Neurobiol. Aging (1996), McGeer, E. G.; McGeer, P. L., Drugs 55:
739-746 (1998)) have been described. These substances inhibit
the synthesis or the action of individual inflammation factors.
It would be desirable, however, to have substances that inhibit
an earlier step in the inflammation process and thus prevent the
development or action of many inflammation factors.
The problem was solved by preparation of benzimidazole
derivatives of general formula I, their tautomeric or isomeric
forms or salts
R3
R2 (I)
N
B A-Y
in which
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RI means a monocyclic or bicyclic C6_12 aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-4 heteroatoms selected from the group that
consists of N, S or 0, whereby the above-mentioned aryl
or heteroaryl group can be substituted with up to three
of the following substituents, independently of one
another:
F, Cl, Br, I,
C (NH) NH2 , C (NH) NHR4 , C (NH) NR4R4' , C (NR4) NH2 , C (NR4) NHR4' ,
C (NR4) NR4R4' ,
XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4,
XCOR4, XC (NOH) R4 , XC (NOR4) R4' , XC (NO (COR4)) R4'
XCN, XCOOH, XCOOR4 , XCONH2 , XCONR4R4', XCONHR4, XCONHOH,
XCONHOR4, XCOSR4
XSR4, XSOR4, XSO 2R4,
SO2NH2 , S02NHR4 , S02NR4R4' ,
NO2, XNH2 , XNHR4 , XNR4R4' , XNHSO2R4 4, XN(SO 2R4) So 2R41'
XNR4S02R4' ,
XNHCOR4, XNHCOOR4, XNHCONHR4, tetrahydro-2,5-
dioxopyrrol-l-yl, 2,5-dihydro-2,5-dioxopyrrol-1-yl,
2,7-dihydro-2,7-dioxoisoindol-l-yl, R4,
whereby two substituents at R1, if they are in ortho-
position to one another, can be linked to one another
in such a way that they jointly form methanediylbisoxy,
ethane-1,2-diylbisoxy, propane-1,3-diyl, butane-l,4-
diyl,
4
R2 means a monocyclic or bicyclic C6_10-aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-4 heteroatoms, selected from the group
that consists of N, S or 0, whereby the above-mentioned
aryl or heteroaryl group can be substituted with up to
three of the following substituents, independently of
one another:
F, Cl, Br, I,
XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4,
XCOR4, XC (NOH) R4, XC (NOR4) R4', XC (NO (COR4) ) R4',
XCOOH, XCOOR4, XCONH2 , XCONHR4, XCONR4R4 1 , XCONHOH ,
XCONHOR4, XCOSR4,
XSR4, XSOR4, XSO2R4, SO2NH21 S02NHR4, S02NR4R4',
NO2 , XNHR4 , XNR4R4 ' , XNHSO2R4 , XN (S02R4) So 2R4' ,
XNR4SO2R4,, tetrahydro-2,5-dioxopyrrol-l-yl, 2,5-
dihydro-2,5-dioxopyrrol-i-yl, 2,7-dihydro-2,7-
dioxoisoindol-i-yl, R4,
whereby two substituents at R2, if they are in ortho-
position to one another, can be linked to one another
in such a way that they jointly form methanediyl-
bisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl,
butane-1,4-diyl,
R3 means one or two substituents, which form,
independently of one another:
hydrogen,
F, Cl, Br, I,
XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4 ,
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XCOR4 , XC (NOH) R 4, XC (NOR4) R4' , XC (NO (COR4) ) R4' ,
XCN, XCOOH, XCOOR4, XCONH2, XCONHR4, XCONR4R4', XCONHOH,
XCONHOR4, XCOSR4, XSR4, XSOR4, XSO2R4, SO2NH2, SO2NHR4,
S02NR4R4' ,
NO2 , XNH2 , XNHR4 , XNR4R4' ,
XNHSO2R4, XNR4SO2R4' , XN (S02R4) (S02R41) ,
XNHCOR4, XNHCOOR4, XNHCONHR4, tetrahydro-2,5-
dioxopyrrol-l-yl, 2,5-dihydro-2,5-dioxopyrrol-l-yl,
2,7-dihydro-2,7-dioxoisoindol-l-yl, or R3 can be R4,
whereby two substituents R3, if they are in ortho-
position to one another, can be linked to one another
in such a way that they jointly form methanediylbisoxy,
ethane-1,2-diylbisoxy, propane-1,3-diyl, or butane-1,4-
diyl,
R4 and R4", independently of one another, mean C1_4
perf luoroalkyl , C1_6 alkyl, C2_6 alkenyl, C2.6 alkinyl, C3.
7 cycloalkyl, (C1.3 alkyl-C3-7 cycloalkyl), C1.3 alkyl-C6.10
aryl, C1_3 alkyl-5 to 10-membered heteroaryl, with 1-4
N, S or 0 atoms, C6-10 aryl or 5- to 10-membered
heteroaryl with 1-4 N, S or.0 atoms, whereby the aryl
and heteroaryl groups can be substituted with one or
two substituents from the group that consists of F, Cl,
Br, CH31 C2H5, NO2, OCH3, OC2H5, CF31 C2F5 or else can
carry an annelated methanediylbisoxy group or ethane-
1,2-diylbisoxy group, and in addition in a 5-membered
cycloalkyl ring, a ring member can be an N or an 0, and
in a 6- or 7-membered cycloalkyl ring, one or two ring
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members can be N and/or 0, whereby ring nitrogens
optionally can be substituted with C1.3 alkyl or C1_3
alkanoyl,
and R , independently of one another, mean C1.6 alkyl, C2_6
R5 5'
alkenyl, C2_6 alkinyl, whereby a carbon atom can be
exchanged for 0, S, SO, SO2, NH, N C1.3 alkyl or N C1.3
alkanoyl,
C3_7 cycloalkyl-C0_3 alkyl, whereby in a 5-membered
cycloalkyl ring, a ring member can be an N or an 0 and
in a 6- or 7-membered cycloalkyl ring, one or two ring
members can be N and/or 0, whereby ring nitrogens
optionally can be substituted with C1.3 alkyl or C1-3
alkanoyl, C6-10 aryl or 5- to l0-membered heteroaryl
with 1-4 heteroatoms from N, S, and 0, whereby the
above-mentioned alkyl, alkenyl and alkinyl chains can
be substituted with one of the previously mentioned
cycloalkyls, aryls or heteroaryls,
whereby all previously mentioned alkyl and cycloalkyl
radicals can be substituted with up to two substituents
from CF3, C2F5, OH, 0 C1.3 alkyl, NH2, NH C1_3 alkyl, NH
C1_3 alkanoyl, N (C1_3 alkyl) 2, N (C1.3 alkyl) (C1.3
alkanoyl), COOH, CONH2, COO C1.3 alkyl, and all
previously mentioned aryl and heteroaryl groups can be
substituted with one or two substituents from the group
that consists of F, Cl, Br, CH31 C2H5, NO2, OCH31 OC2H5,
CF3, and C2F5 or else can carry an annelated
methanediylbisoxy or ethane-1,2-diylbisoxy group,
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or R5 and R5' together with the nitrogen atom form a 5-
to 7-membered heterocyclic compound, which can contain
another oxygen, nitrogen or sulfur atom and can be
substituted with C1.4 alkyl, C1_4 alkoxy-C0_2 alkyl, C1_4
alkoxy-carbonyl, aminocarbonyl or phenyl,
A means C1-10 alkanediyl, C2.10 alkenediyl, C2-10 alkinediyl,
(CO-5 alkanediyl-C3_7 cycloalkanediyl-C0_5 alkanediyl),
whereby in a 5-membered cycloalkyl ring, a ring member
can be an N or an 0, and in a 6- or 7-membered
cycloalkyl ring, one or two ring members can be N
and/or 0, whereby ring nitrogens optionally can be
substituted with C1_3 alkyl or C1_3 alkanoyl, whereby in
the above-mentioned aliphatic chains, a carbon atom or
two carbon atoms can be exchanged for 0, NH, N C1.3
alkyl, N C1.3 alkanoyl, and whereby alkyl or cycloalkyl
groups can be substituted with up to two substituents
consisting of =0, OH, 0 C1.3 alkyl, NH2, NH C1.3 alkyl,
NH C1.3 alkanoyl, N (C1.3 alkyl)2, N(Cl_3 alkyl) (C1.3
alkanoyl),
B means COOH, COOR5, CONH2, CONHNH2, CONHR5, CONR5R5',
CONHOH, CONHOR5,
SO3H, SO2NH21 SO2NHR5, S02NR5R5,
POSH , PO (OH) (OR5), PO (OR5) (OR5') , PO (OH) (NHR5),
PO (NHR5) (NHR51) ,
tetrazolyl,
in each case bonded to a carbon atom of group A,
or the entire group Y-A-B N(S02R4) (So 2R4') or NHS02R4'
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X means a bond, CH2, (CH2) 2, CH (CH3) , (CHZ) 3, CH (CH2CH3) ,
CH (CH3) CHZ , CH2CH (CH3) ,
Y means 0, NH, NR4, NCOR4, NS02R4,
provided that if Y means NH, NR4, NCOR4 or NS02R4, and
a) substituent R2 contains a nitrogen-containing,
saturated heterocyclic compound, this heterocyclic
compound is not substituted in the imine nitrogen with
H, methyl, ethyl, propyl or isopropyl,
or
b) in optionally present groups XNHR4- or XNR4R4' of
substituent R2, R4 and/or R4' does not mean C1_4 alkyl,
provided that B does not mean COOH, SO3H, P03H2 or tetrazolyl at
the same time, and R1 and R2, independently of one another, mean
C5.6 heteroaryl or phenyl, if the latter, independently of one
another, are unsubstituted, or are substituted simply with C1_6
alkyl, C1_4 perfluoroalkyl, 0 C1.6 alkyl, 0 C1.4 perfluoroalkyl,
COOH, COO C1_6 alkyl, CO C1_6 alkyl, CONH2, CONHR4, NO2, NH21 NHCOR4,
NHSO2R4, or with 1 or 2 halogen atoms from the group that
consists of F, Cl, Br,. and I, and
whereby the following compounds are excluded:
[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]acetic acid methyl
ester,
5-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid
methyl ester,
4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butanoic acid
ethyl ester,
9
5- [ [i- (4-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] -
pentanoic acid methyl ester,
6-[[1-(4-nitrophenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid methyl ester,
5-[[1-(4-aminophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]pentanoic acid methyl ester,
5- [ [1- [4- [ [ (4-chlorophenyl) sulfonyl] amino] phenyl] -2-phenyl-
1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester,
5-[[1-[4-[(acetyl)amino]phenyl]-2-phenyl-1H-benzimidazol-6-
yl]oxy]pentanoic acid methyl ester,
5-[[1-(3-nitrophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]pentanoic acid methyl ester,
6-[[1-(3-nitrophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester,
5-[[1-(3-aminophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]pentanoic acid methyl ester,
5- [ [l- [3- [ [ (4-chlorophenyl) sulfonyl] amino] phenyl] -2-phenyl-
1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester,
5-[[1-[3-[(acetyl)amino]phenyl]-2-phenyl-1H-benzimidazol-6-
yl]oxy]pentanoic acid methyl ester.
The physiologically compatible salts can be formed with
inorganic and organic acids, such as, for example, oxalic acid,
lactic acid, citric acid, fumaric acid, acetic acid, maleic acid,
tartaric acid, phosphoric acid, HC1, HBr, sulfuric acid, p-
toluenesulfonic acid, and methanesulfonic acid.
For salt formation of acid groups, inorganic or organic
bases are also suitable that are known for the formation of
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physiologically compatible salts, such as, for example, alkali
hydroxides, sodium and potassium hydroxide, alkaline-earth
hydroxides such as calcium hydroxide, ammonia, amines such as
ethanolamine, diethanolamine, triethanolamine, N-methylglucamine,
tris-(hydroxymethyl)-methylamine.
An "aryl group" is defined in particular as an optionally
substituted phenyl group or biphenyl, naphthyl, indane or
fluorenyl.
A heteroaryl group is built up of 5-10 skeleton atoms and
can contain 1-4 heteroatoms. Heteroatoms are oxygen (0),
nitrogen (N) and sulfur (S). Examples of a monocyclic heteroaryl
group are pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, furazanyl,
pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. Examples of a
bicyclic heteroaryl group are thienoimidazolyl, indolyl,
isoindolyl, benzothiophenyl, benzofuranyl, benzimidazolyl,
indazolyl, imidazopyridinyl, purinyl, quinolyl, isoquinolyl,
phthalazinyl, quinazolinyl, quinaxolinyl, cinnolinyl,
naphthyridinyl and pteridinyl. If the aryl groups or heteroaryl
groups are part of R1, the binding to N of the benzimidazole is
carried out via a carbon atom.
Alkyl groups can be straight-chain or branched. Examples
are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-
butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl,
sec-hexyl, heptyl, octyl, nonyl, and hexyl.
Perfluorinated alkyls are preferably CF3 and C2F5, and
alkanoyls are preferably formyl, acetyl and propionyl.
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Alkenyl groups can be straight-chain or branched. For
example, the following radicals can be mentioned: vinyl, 2-
propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl-l-propenyl,
2-methyl-2-propenyl, 3-methyl-2-propenyl.
Alkinyl groups can be straight-chain or branched. Examples
of this are: ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, and 2-
butinyl.
Cycloalkyl groups are defined respectively as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
As a saturated heterocyclic compound or as a cycloalkyl with
1 or more heteroatoms, there can be mentioned, for example:
piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine,
hexahydroazepine as well as 2,6-dimethylmorpholine, N-phenyl-
piperazine, methoxymethylpyrrolidine, whereby the linkage with a
carbon that is adjacent to the ring can be carried out with
optionally present ring nitrogens.
As alkanes, alkenes and alkines for A, there can be
mentioned, for example:
Straight-chain or branched alkylene with 1-8 C atoms, such
as: methylene, ethylene, propylene, butylene, pentylene, etc.,
1-methylethylene, 1-ethylethylene, 1-methylpropylene, 2-
methylpropylene, 1-methylbutylene, 2-methylbutylene, 1-
ethylbutylene, 2-ethylbutylene, 1-methylpentylene, 2-
methylpentylene, 3-methylpentylene, etc.
Straight-chain or branched alkenylene and alkinylene with 2-
8 C atoms are alkenylene groups or alkinylene groups with double
and triple bonds in all possible positions as well as with all
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possible methyl or ethyl substitutions. In these radicals, in
each case one or two C atoms can be exchanged for 0, NH, NC1-3-
alkyl or N-C1_3-alkanoyl, whereby the exchanged group is separated
from Y by at least 2 C atoms.
If two radicals are in ortho-position, they can form a
common ring with the adjacent aromatic compounds. Compounds in
which N, 0 or S atoms are bonded to olefinic or acetylenic
multiple bonds or in which several N, 0, S or halogen atoms are
bonded to the same aliphatic carbon atom or in which N-, 0- or S
atoms are bonded directly to one another, are excluded, if these
linkages are not explicitly defined, for example, in the
functional groups or in heteroaromatic compounds that are
mentioned in the claim.
Preferred are the benzimidazoles in which:
R1 means a monocyclic or bicyclic C6-12 aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-2 heteroatoms selected from the group that
consists of N, S or 0, whereby the above-mentioned aryl
or heteroaryl group can be substituted with up to three
of the following substituents, independently of one
another:
F, Cl, Br,
XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4,
XCOR4, XCN, XCOOH, XCOOR4, XCONH2 , XCONR6R4 1 , XCONHR4 ,
XCONHOH, XCONHOR4, XCOSR4, XSR4, NO2, XNHR4, XNR4R41, R4,
whereby two substituents at R1, if they are in ortho-
position to one another, can be linked to one another
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in such a way that they jointly form methanediylbisoxy,
ethane-1,2-diylbisoxy, propane-1,3-diyl, or butane-l,4-
diyl.
Preferred are also benzimidazoles, in which
R2 means a monocyclic or bicyclic Cb_1o-aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-2 heteroatoms selected from the group that
consists of N, S or 0, whereby the above-mentioned aryl
or heteroaryl group can be substituted with up to three
of the following substituents, independently of one
another:
F, Cl, Br,
XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4,
XCOR4, XC (NOH) R4, XC (NOR4) R4,, XC (NO (COR4) ) R4`,
XCOOH, XCOOR4, XCONH2 , XCONHR4, XC0NR4R4 ` , XCONHOH,
XCONHOR4, XCOSR4,
XSR4, XSOR4, XS02R4, SO2NH2, SO2NHR4, S02NR4R41,
NO2, XNHR4, XNR4R4I, XNHS02R4, XN(S02R4)S02R4`, XNR4SO2R41,
R4
whereby two substituents at R2, if they are in ortho-
position to one another, can be linked to one another
in such a way that they jointly form methanediylbisoxy,
ethane-1,2-diylbisoxy, propane-1,3-diyl, butane-1,4-
diyl.
14
Also preferred are benzimidazoles of general formula I, in
which
R3 means one or two substituents, which, independently of
one another, can be:
hydrogen, F, Cl, Br,
XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4,
XCOR4, XC (NOH) R4, XC (NOR4) R4' , XC (NO (COR4) ) R4' ,
XCN, XSR4, XSOR4, XSO2R4, SO2NH2, SO2NHR4, SO2NR4R4' ,
NO2, XNH2 , XNHR4 , XNR4N4' ,
XNHSO2R4' XNR4SO2R4' , XN (SO2R4) SO2R4' ,
XNHCOR4, XNHCOOR4, XNHCONHR4, or R4, whereby two
substituents R3, if they are in ortho-position to one
another, can be linked to one another in such a way
that they jointly form methanediylbisoxy, ethane-1,2-
diylbisoxy, propane-1,3-diyl, or butane-1,4-diyl.
Preferred are also benzimidazoles of general formula I, in
which
R4 and R4', independently of one another, mean CF31 C2F5, C1_4-
alkyl, C2.4-alkenyl, C2_4-alkinyl, C3_6-cycloalkyl, (C1_3-
alkyl-C3.6-cycloalkyl), phenyl or 5- to 6-membered
heteroaryl with 1-2 N, S or 0 atoms, whereby the phenyl
and heteroaryl groups can be substituted with one or
two substituents from the group that consists of F, Cl,
Br, CH3 1 C2H5 , OCH3 1 OC2H5 , CF3 , and C2F5 1
and in addition in a 5-membered cycloalkyl ring, a ring
member can be an N or an 0, and in a 6-membered
cycloalkyl ring, one or two ring members can be N
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and/or 0, whereby ring nitrogens optionally can be
substituted with C1_3 alkyl or C1_3 alkanoyl.
Also preferred are benzimidazoles of general formula I, in
which
R5 and R5', independently of one another, can be C1_6 alkyl,
whereby a carbon atom can be exchanged for 0, NH, N C1-3
alkyl, N C1_3 alkanoyl,
C3_7 cycloalkyl-CO.3 alkyl, whereby in a 5-membered
cycloalkyl ring, a ring member can be an N or an 0, and
in a 6- or 7-membered cycloalkyl ring, one or two ring
members can be N and/or 0, whereby ring nitrogens
optionally can be substituted with C1.3 alkyl or C1-3
alkanoyl, whereby the above-mentioned C1.6 alkyl part
can be substituted with one of the previously mentioned
cycloalkyls or else a 5- to 6-membered heteroaromatic
compound with 1-2 heteroatoms, selected from N, S or 0,
whereby all previously mentioned alkyl and cycloalkyl
parts can be substituted with up to two substituents
that consist of CF31 OH, 0 C1.3 alkyl, and the
previously mentioned'heteroaryl groups with one or two
substituents that consist of F, Cl, CF3, CH3, C2H5, OCH31
OC2H5, or R5 and R5' together with the nitrogen atom form
a 5- to 7-membered heterocyclic compound, which can
contain another oxygen, nitrogen or sulfur atom and can
be substituted with C1.4-alkyl, C1.4-alkoxy-C0_2 alkyl, C1_
4-alkoxy-carbonyl, aminocarbonyl or phenyl.
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Preferred are also benzimidazoles of general formula I, in
which
A means C1_10 alkanediyl, C2_1U alkenediyl, C2_10 alkinediyl,
(C0.5 alkanediyl-C3_7 cycloalkanediyl-C0.5 alkanediyl) ,
whereby in a 5-membered cycloalkyl ring, a ring member
can be an N or an 0, or in a 6- or 7-membered
cycloalkyl ring, one or two ring members can be N
and/or 0, whereby ring nitrogens optionally can be
substituted with C1.3 alkyl or C1_3 alkanoyl,
whereby in the above-mentioned aliphatic chains, a
carbon atom or two carbon atoms can be exchanged for 0,
NH, N C1.3 alkyl, or N C1_3 alkanoyl.
Also preferred are benzimidazoles of general formula I, in
which
B means COOH, COOR5, CONH2, CONHR5, CONR5R51, CONHOH,
CONHOR5 or tetrazolyl,
in each case bonded to a carbon atom of group A.
B in the meaning of COO R5, CONH2, CONH R5, CON R5 or R5' is
especially preferred.
Preferred are also benzimidazoles of general formula I, in
which
X means a bond or methylene.
Preferred are also benzimidazoles of general formula I, in
which
Y means 0.
In particular, R1 and R2, independently of one another,
mean phenyl or 5- to 6-membered heteroaryl, with 1-2
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heteroatoms such as N, 0 or S atoms, which can be
substituted with F, Cl, Br, cyano, C1_4 alkyl, C1_4
alkoxy, methylenedioxy, C1_4 alkylthio, NO2, CF3, NH2, NH
(C1.3 alkyl), N (C1-3 alkyl) 2.
The meaning of H, F, Cl, OH, C1.4-alkoxy, C1_4-alkyl,
NO2, NH2, NH-C1_4-alkanoyl NH-S02-benzyl or NH-S02-
phenyl, whereby the phenyl radical can be substituted
with F, C1, Br, C1_4-alkyl, C1_4-alkoxy, CF3 or
acetylamino, is especially preferred for R3.
Especially preferred are the following benzimidazoles:
[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]acetic acid
isopropyl ester
3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid
methyl ester
2-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]propanoic acid
methyl ester
4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butanoic acid
isopropyl ester
5-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid
isopropyl ester
6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid
methyl ester
6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid
isopropyl ester
6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide
N-methoxy-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
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18
N-(phenylmethoxy)-6-[(1,2-diphenyl-lH-benzimidazol-6-
yl) oxy] hexanamide
N-hydroxy-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
7-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]heptanoic acid
methyl ester
6-[[l-(3-nitrophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[2-phenyl-l-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-
6-yl]oxy]hexanoic acid methyl ester
6-[[2-phenyl-l-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-
6-yl]oxy]hexanoic acid isopropyl ester
6-[(1-(3-cyanophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(3-cyanophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[1-(3-cyanophenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[1-(4-cyanophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-cyanophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-([1-(3-chiorophenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(3-chiorophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
CA 02396227 2002-07-04
19
6-[[1-(4-chlorophenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-chlorophenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[1-(3-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(3-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(3,5-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(3,5-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[1-(3-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(3,4-dimethoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-[3,4-(methylenedioxy)phenyl]-2-phenyl-lH-benzimidazol-
6-yl]oxy]hexanoic acid methyl ester
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20
6-[[1-[3,4-(methylenedioxy)phenyl]-2-phenyl-1H-benzimidazol-
6-yl] oxy] hexanoic acid
6-[[2-phenyl-l-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-phenyl-l-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[2-phenyl-l-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6- ([1- [4- (N,N-dimethylamino)phenyl] -2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6- [ [1- [4- (N,N-dimethylamino)phenyl] -2-phenyl-1H-
benzimidazol-6-yl]oxy]hexanoic acid
6-[[l-phenyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-
6-yl]oxy]hexanoic acid isopropyl ester
6-[[2-(3-chlorophenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[(2-(3-chlorophenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[(2-(4-chlorophenyl)-l-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-(4-chlorophenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[(2-(4-methylphenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-(4-methylphenyl)-l-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
CA 02396227 2002-07-04
21
6-[(1-phenyl-2-(4-pyridinyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl)oxy]hexanoic
acid methyl ester
6-[(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester
6- [ [5- [ [ (4-bromophenyl) sulfonyl] amino] -1, 2-diphenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6 - [ [ 5 - [ [ (4 - chlorophenyl) sul f onyl. ] amino ] -1T, 2 -diphenyl -1H -
benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6- [ [5- ([ (4-chlorophenyl) sulfonyl] amino] -1, 2-diphenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6- ((1, 2-diphenyl-5- [ [ (3-methylphenyl) sulfonyl] amino] -1H-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6- [ [1, 2-diphenyl-5- [ ((4-methylphenyl) sulfonyl] amino] -1H-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6- [ [1, 2-diphenyl-5- [ ((4-methoxyphenyl) sulfonyl] amino] -1H-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6- ([1,2-diphenyl-5- [ [ [ (4-trifluoromethyl)phenyl] sulfonyl] -
amino]-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6- [ [5- [ [ [4- (acetylamino) phenyl] sulfonyl] amino] -1, 2 -diphenyl-
1H-benzimidazol-6-yl]oxy]-hexanoic acid isopropyl ester
6-[[5- [ (bis (3-chlorophenyl) sulfonyl] amino] -1, 2-diphenyl-1H-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6-[[1,2-diphenyl-5-[(propylsulfonyl)amino]-1H-benzimidazol-
6-yl]oxy]hexanoic acid isopropyl ester
CA 02396227 2002-07-04
CA 02396227 2002-07-04
22
6-[[5-[(benzylsulfonyl)amino]-1,2-diphenyl-lH-benzimidazol-
6-yl]oxy]hexanoic acid isopropyl ester
2-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic
acid methyl ester
3- [2- [ (1, 2-diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] -
propanoic acid methyl ester
6-[[1-(3-nitrophenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid ethyl ester
6-[[4-acetyl-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester
6-[[2-phenyl-l-(4-(thiomethyl)phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester
6-[(2-phenyl-l-[(4-(thiomethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-phenyl-l-(3-thienyl)-1H-benzimidazol-5-yl]oxy] hexanoic
acid methyl ester
6-[[2-phenyl-l-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butanoic acid
methyl ester
N-(phenylmethoxy)-6-[[2-phenyl-l-(3,4,5-trimethoxyphenyl)-
1H-benzimidazol-6-yl]oxy]-hexanamide
N,N-dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
23
N-isopropyl-6-[(i,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]-1-pyrrolidin-l-
ylhexan-l-one
5- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -i, 2-diphenyl-lH-
benzimidazol-6-yl]oxy]pentanoic acid methyl ester
6- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -1- (4-methylphenyl) -
2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -
2-phenyl-iH-benzimidazol-6-yl]oxy] hexanoic acid methyl ester
6-[[4-(acetyloxy)-1-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6-[(4-hydroxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[4-hydroxy-i-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[7-methyl-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-phenyl-l-(3-pyridyl)-1H-benzimidazol-5-yl]oxy] hexanoic
acid methyl ester
6-[[2-phenyl-l-(3-pyridyl)-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
6-[[2-phenyl-l-(4-pyridyl)-1H-benzimidazol-6-yl]oxy] hexanoic
acid methyl ester
6-[[2-(4-fluoro-phenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
CA 02396227 2002-07-04
24
6-[[2-(4-methoxyphenyl)-l-phenyl-1H-benzimidazol-6-yl]oxy]-
hexanoic acid methyl ester
6-[[2-(4-bromophenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-[4-(trifluoromethyl)phenyl]-1-phenyl-lH-benzimidazol-
6-yl]oxy]hexanoic acid methyl ester
6-[[l-phenyl-2-(benzothien-2-yl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[l-phenyl-2-(benzothien-2-yl)-1H-benzimidazol-6-
yl]-oxy] hexanoic acid
6-[[5-hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[5-hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy]hexanoic acid
6-[[5-methoxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[5-hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[5-methoxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -1- (3,4-
dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy] hexanoic acid
methyl ester benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6- [ [5- [ ( (4-chlorophenyl) sulfonyl] amino] -2- (4-fluorophenyl) -
1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl
ester
CA 02396227 2002-07-04
25
6 - [ [ 5 - [ [ (4 - chlorophenyl) sul f onyl ] amino] -1- (4 -methoxyphenyl) -
2-(4-methoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl
ester
4 - [ [ 5 - [ [ (4 - chlorophenyl) sul f onyl ] amino ] -1- (4 -methoxyphenyl)
-
2-phenyl-1H-benzimidazol-6-yl]oxy]butanoic acid methyl ester
5- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -
2-phenyl-1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester
5- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -1, 2-diphenyl-1H-
benzimidazol-6-yl]oxy]pentanoic acid methyl ester
6- [ [5- [ [ (4- (trifluoromethyl)phenyl) sulfonyl] amino] -1- (4-
methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester
6- ([5- [ [ (4-chlorophenyl) sulfonyl] methylamino] -1- (4-
methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester
6-[[1-(indan-5-yl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6- [[l-(indan-5-yl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[(1-(3-fluorophenyl)-2.-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-(4-nitrophenyl)-1-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[l-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
N-(cyclopropylmethoxy)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
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26
N-isobutoxy-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
N-(cyclopropylmethoxy)-6-[2-phenyl-l-(3,4,5-
trimethoxyphenyl)-1H-benzimidazol-6-yl)oxy]-hexanamide
N-isobutoxy-6-[2-phenyl-l-(3,4,5-trimethoxyphenyl)-1H-
benzimidazol-6-yl)oxy]hexanamide
N-(2-methoxyethyl)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
N-(3-methoxypropyl)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
N-isobutyl-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]-1-morpholin-l-
ylhexan-l-one
N,N-di(-2-methoxyethyl)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
N-isopentyl-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
N-(pyridin-2-yl)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
N-(pyridin-3-yl)-6-((1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
N-isopropyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanamide
N,N-dimethyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy] hexanamide
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27
N,N-diethyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanamide
N-isobutyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-
benzimidazol-6-yl]oxy]hexanamide
N-cyclopropyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanamide
N-cyclobutyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanamide
N-tent-butyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanamide
(R)-6-[[1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]1-(2-methoxymethyl)-pyrrolidin-l-ylhexan-l-one
N-(3-imidazol-i-yl-propyl)-6-[[1-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl]oxy]hexanamide
N-(2-pyridin-2-ylethyl)-6-[[1-(3,4-dimethylphenyl)-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanamide
N-(3-methoxypropyl)-6-[[1-(indan-5-yl)-2-phenyl-iH-
benzimidazol-6-yl]oxy]heptanamide
6-[[1-(4-methylphenyl)-2-(3-pyridyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-(4-pyridyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-(2-thienyl)-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
CA 02396227 2002-07-04
CA 02396227 2002-07-04
28
6-[(2-(3-indolyl)-1-(4-methylphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-(2-furyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6- [ [1- (4-methylphenyl) -2- (3-furyl),-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-(5-methyl-2-thienyl)-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6-[[1-(4-methylphenyl)-2-(3-methyl-2-thienyl)-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester
The benzimidazole derivatives according to the invention
inhibit the activation of microglia and can therefore be used for
the production of a pharmaceutical agent for treating or for
preventing diseases that are associated with a inicr'oglia.
Microglia are defined here as the macrophages of the brain.
This action is surprising since to date benzimidazole
derivatives had been described only for the treatment of
thromboses and arteriosclerosis (RP0531883, W095/07263,
EP0104727, WO97/12613), cystitis (W097/33873) and diseases that
are associated with a iS-amyloid peptide (US5,552,426) and
increased activation of Ca-channels (EP520200), but an effect on
microglia is not known.
AMENDED
SHEET
CA 02396227 2002-07-04
29
The invention also relates to the use of a benzimidazole of
general formula II
R3
I r' R2
F~=A~
NZ~
RI
in which
x0 means a monocyclic or bicyclic C6_12-aryl group or a
monocyclic or bicyclic 5- to l0-membered heteroaryl
group with 1-4 heteroatoms that are selected from the
group that consists of N, S or 0, whereby the above-
mentioned aryl or heteroaryl group can be substituted
with up to three of the following substituents,
independently of one another:
F, Cl, Br, 1, C(NH)NH2, C(NH)NHR4, C(NH)NR4R4',
C (NR`) NHZ , C (NR`) NKR4' , C (NR4) NR4R'' , XOH, XOR`, XOCOR' ,
XOCONHR4, XOCOOR4, XCOR4 , XC (NOH) R4 , XC (NOR4) R" ,
XC (NO (COR4) ) R4, , XCN, XCOOH, XCOOR4, XCONH2,
XCONR'R4' , XCONHR4, XCONHOH, XCONROR4, XCOSR`, XSR4,
XSOR`, XSO2R4, S02NH21 S02NHR4, SOZNR"R4' , NO2, XNH2, XNHR4,
XNR4R4', XNHSO2R4, XN (SO2R4) (SO2R4') , XNR4SO2R4' ,
XNHCOR`', XNHCOOR4 ,
AMENDED
SHEET
CA 02396227 2002-07-04
XNHCONHR4, tetrahydro-2,5-dioxopyrrol-1-yl, 2,5-
dihydro-2,5-dioxopyrrol-l-yl, 2,7-dihydro-2,7-
dioxoisoindol-l-yl, R4, whereby two substituents at R1,
if they are in ortho-position to one another, can be
linked to one another in such a way that they jointly
form methanediylbisoxy, ethane-l,2-diylbisoxy, propane-
1,3-diyl, butane-1,4-diyl,
R2 means a monocyclic or bicyclic C6_10 aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-4 heteroatoms selected from the group that
consists of N, S or 0, whereby the above-mentioned aryl
or heteroaryl group can be substituted with up to three
of the following substituents, independently of one
another:
F, Cl, Br, I, C(NH)NH,, C (NH) NHR4, C (NH) NR4R4' ,
C (NR4) NH2 , C (NR4) NHR41 ,
C (NR4) NR4R4', XOH, XOR4, XOCOR4, XOCONHR4, XOCOOR4,
XCOR4, XC (NOH) R4, XC (NOR4) R41, XC (NO (COR4) ) R41, XCN,
XCOOH, XCOOR4,
XCONH2, XCONR4R4' , XCONHR4, XCONHOH, XCONHOR4, XCOSR4,
XSR4, XSOR4, XSO2R4, SO2NH2, S02NHR4, S02NR4R41,
NO2 , XNH2 , XNHR4 ,
XNR4R4' , XNHSO2R4, XN (S02R4) (S02R41) , XNR4SO2R4' , XNHCOR4,
XNHCOOR4 ,
XNHCONHR4, tetrahydro-2,5-dioxopyrrol-1-yl, 2,5-
dihydro-2,5-dioxopyrrol-1-yl,
AMENDED
SHEET
CA 02396227 2002-07-04
31
2,7-dihjrdro-2,7-dioxoisoindol-1-yl, R4, whereby two
substituents at R2, if they are in ortho-position to
one another, can be linked to one another in such a way
that they jointly form methanediylbisoxy, ethane-1,2-
diylbisoxy, propane-1,3-diyl, butane-1,4-diyl,
R3 stands for one or two substituents, that mean,
independently of one another:
hydrogen, F, Cl, Br, I, XOH, XOR4, XOCOR4, XOCONHR4,
XOCOOR4 ,
XCOR4, XC (NOH) R4, XC (NOR4) R4' , XC (NO (COR4)) R4' ,
XCN, XCOOH, XCOOR4,
XCONH2, XCONHR4, XCONR4R4' , XCONHOH, XCONHOR4, XCOSR4,
XSR4,
XSOR4, XSO2R4, SO2NH21 S02NHR4, S02NR4R4', NO2, XNH2, XNHR4,
XNR4R4' ,
XNHS02R4 , XNR4S02R4' , XN(S02R4) (S02R4') , XNHCOR4, XNHCOOR4,
XNHCONHR4, tetrahydro-2,5-dioxopyrrol-l-yl, 2,5-
dihydro-2,5-dioxopyrrol-i-yl,
2,7-dihydro-2,7-dioxoisoindol-l-yl, R4, whereby two
substituents R3, if they are in ortho-position to one
another, can be linked to one another in such a way
that they jointly form methanediylbisoxy, ethane-1,2-
diylbisoxy, propane-1,3-diyl, butane-1,4-diyl,
R4 and R4', independently of one another, mean C1_4
perfluoroalkyl, C1_6 alkyl, C2_6 alkenyl, C2_6 alkinyl, C3-
7 cycloalkyl, (C1_3 alkyl-C3_7 cycloalkyl) , C1_3 alkyl-C6-10
aryl, C1_3 alkyl 5- to 10-membered heteroaryl with 1-4
CA 02396227 2002-07-04
32
N, S or 0 atoms heteroaryl, 06.10-aryl or 5- to 10-
membered heteroaryl with 1-4 N. S or 0 atoms, whereby
the Cb_1o-aryl and heteroaryl groups can be substituted
with one or two substituents from the group that
consists of F, Cl, Sr, M.- CZHS, NO2, OCH31 OC2H5, CF31
CZFS or else can carry an annelated methanediylbisoxy
group or ethane-1,2-diylbisoxy group, whereby in a 5-
membered cycloalkyl ring, a ring member can be an N or
an 0, and in a 6- or 7-membered cycloalkyl ring, one or
two ring members can be N and/or 0, whereby ring
nitrogens optionally can be substituted with Cl-, alkyl
or C,.3 alkanoyl,
RS and RS`, independently of one another, mean hydrogen, CI-6
alkyl, C2.6 alkenyl, C2.6 alkinyl, whereby a carbon atom
can be exchanged for 0, S, SO, SO2, NH, N CJ-3 alkyl or
N C,_3 alkanoyl,
C3.7 cycloalkyl-c0.3 alkyl, whereby in a 5-membered
cycloalkyl ring, a ring member can be an N or an 0 and
in a 6- or 7-membered cycloalkyl ring, one or two ring
members can be N and/or 0, whereby ring nitrogens
optionally can be substituted with C,_3 alkyl or C,.3
alkanoyl.
C6_10-aryl or 5- to 10-membered heteroaryl with 1-4
heceroatoms from N. S, and 0, whereby the above-
mentioned alkyl, alkenyl and alkinyl chains can be
substituted with one of the previously mentioned
cycloalkyls, aryls or heteroaryls,
33
whereby all previously mentioned alkyl and cycloalkyl
radicals with up to two substituents consisting of CF3,
C2F51 OH, 0 C1_3 alkyl, NH2, NH C1.3 alkyl, NH C1_3
alkanoyl, N (C1.3 alkyl) 2 N (C1.3 alkyl) (C1.3 alkanoyl) ,
COOH, CONH2, COO C1_3 alkyl and all previously mentioned
aryl and heteroaryl groups can be substituted with one
or two substituents from the group that consists of F,
Cl, Br, CH3, C2H5, NO2, OCH31 OC2H5, CF31 C2F5 or else can
carry an annelated methanediylbisoxy, ethane-l,2-
diylbisoxy group,
or R5 and R5' together with the nitrogen atom form a 5-
to 7-membered heterocyclic compound, which can contain
another oxygen, nitrogen or sulfur atom and can be
substituted with C1.4-alkyl, C1.4-alkoxy-C0_2 alkyl, C1.4-
alkoxy-carbonyl, aminocarbonyl or phenyl,
A means C,.10 alkanediyl, C2-10 alkenediyl, C2-10 alkinediyl,
(C0.5 alkanediyl-C3_7 cycloalkanediyl-C0_5 alkanediyl),
(C0.5 alkanediylarylene-C0.5 alkanediyl), (C0.5
alkanediyl-heteroarylene-C0.5 alkanediyl),
whereby the aryl and heteroaryl groups can be
substituted with one or two substituents that consist
of F, Cl, Br, CH3, C2H5, NO2, OCH3, OC2H5, CF31 C2F5,
whereby in a 5-membered cycloalkyl ring, a ring member
can be an N or an 0, and in a 6- or 7-membered
cycloalkyl ring, one or two ring members can be N
and/or 0, whereby ring nitrogens optionally can be
substituted with C,.3-alkyl or C,.3-alkanoyl,
CA 02396227 2002-07-04
34
whereby in the above-mentioned aliphatic chains, a
carbon atom or two carbon atoms can be exchanged for 0,
NH, NR4, NCOR4, NSO2R4,
and whereby alkyl or cycloalkyl groups can be
substituted with up to two'substituents consisting of
F, OH, OR4, OCOR4, =0, NH2, NR4R4`, NHCOR4, NHCOOR4,
NHCONHR4, NHSO2R4SH, SR4,
B means hydrogen, OH, OCORS , OCONHRS , OCOORS , CORS ,
C (NOH) R5, C (NOR5) R5`,
C (NO (CORS)) R5 ` , COOH, COOR5, CONH2 , CONHNH2 , CONHRS ,
CONR5R5` ,
CONHOH, CONHOR5, SO3H, SO2NH2, SO2NHR5, SO2NR1R5` ,
POSH, PO (OH) (ORS) , PO (OR5) (ORS`) , PO (OH) (NHR5) ,
PO (NHR5) (NHR51) ,
tetrazolyl, respectively bonded to a carbon atom of
group A,
or the entire group Y-A-B N (S02R4) So 2R4') or NHS02R4,
% means a bond, CH2 , (CH2) 2' CH (CH3) , (CH2) 31 CH (CH2CH3) ,
CH (CH3) CH2, CH2CH (CH3) ,
Y means a bond, 0, S, SO, SO2, NH, NR4, NCOR4, NSO2R4,
for the production of a pharmaceutical agent for treating or
preventing diseases that are associated with a microglia
activation.
In addition to the new compounds of general formula I,
general formula II also comprises known compounds (EP 0 531 883,
DE 4330959). The compounds of general formula II according to
CA 02396227 2002-07-04
35
the invention inhibit the activation of the microglia activation.
This action is also new for the known compounds.
Preferred is the use of compounds of general formula II,
whereby
R1 means a monocyclic or bicyclic aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-2 heteroatoms selected from the group that
consists of N, S or 0, whereby the above-mentioned aryl
or heteroaryl group can be substituted with up to three
of the following substituents, independently of one
another:
F, Cl, Br,
XOH, XOR4 , XOCOR4, XOCONHR4 , XOCOOR4,
XCOR4, XCN, XCOOH, XCOOR4, XCONH2, XCONR4R41 , XCONHR4,
XCONHOH,
XCONHOR4, XCOSR4, XSR4, NO2, XNHR4, XNR4R41 , R4,
whereby two substituents at RI, if they are in ortho-
position to one another, can be linked to one another
in such a way that they jointly form methanediylbisoxy,
ethane-1,2-diylbisoxy, propane-1,3-diyl, butane-1,4-
diyl.
Also preferred is the use of compounds of general formula
II, whereby
R2 means a monocyclic or bicyclic aryl group or a
monocyclic or bicyclic 5- to 10-membered heteroaryl
group with 1-2 heteroatoms selected from the group that
consists of N, S or 0, whereby the above-mentioned aryl
CA 02396227 2002-07-04
36
group or heteroaryl group can be substituted with up to
three of the following substituents, independently of
one another:
F, Cl, Br, XOH, XOR4 , XOCOR4 , XOCONHR4, XOCOOR4 ,
XCOR4, XC (NOH) R4,
XC (NOR4) R4', XC (NO (COR4) ) R4', XCN, XCOOH, XCOOR4, XCONH2,
XCONR4R4' ,
XCONHR4, XCONHOH, XCONHOR4, XCOSR4, XSR4, XSOR4, XSO2R4,
SO2NH2, S02NHR4, S02NR4R4" NO2, XNH2, XNHR4, XNR4R41,
XNES02R4,
XN (S02R4) (S02R41) , XNR4SO2R41 , XNHCOR4, XNHCOOR4,
XNHCONHR4 , R4 ,
whereby two substituents at R2, if they are in ortho-
position to one another, can be linked to one another
in such a way that they jointly form methanediylbisoxy,
ethane-1,2-diylbisoxy, propane-1,3-diyl, butane-l,4-
diyl.
Also preferred is the use of compounds of general formula
II, whereby
R3 stands for one or two substituents, which,
independently of one another, mean:
hydrogen, F, Cl, Br, XOH, XOR4, XOCOR4, XOCONHR4,
XOCOOR4 ,
XCOR4, XC (NOH) R4, XC (NOR4) R4, , XC (NO (COR4) ) R4',
XCN, XSR4, XSOR4,
XS02R4, SO2NH2, SO2NHR4, S02NR4R4` , NO2, XNH2, XNHR4,
XNR4R41,
CA 02396227 2002-07-04
37
XNHSO2R4 , XNR4SO2R4' , XN (SO2R4) (SO2R4') , XNHCOR4, XNHCOOR4,
XNHCONHR4, or R4, whereby two substituents R3,
if they are in ortho-position to one another, can be
linked to one another in such a way that they jointly
form methanediylbisoxy, ethane-l,2-diylbisoxy, propane-
1,3-diyl, butane-1,4-diyl.
Also preferred is the use of compounds of general formula II
whereby
R4 4'
and R, independently of one another, mean CF3, C2F51 C1_4
alkyl, C2.4 alkenyl, C2_4 alkinyl, C3_6 cycloalkyl, (C1.3
alkyl-C3_6 cycloalkyl), C1=3 alkylaryl, C1.3
alkylheteroaryl, monocyclic aryl or 5- to 6-membered
heteroaryl with 1-2 N, S or 0 atoms, whereby the aryl
and heteroaryl groups can be substituted with one or
two substituents from the group that consists of F, Cl,
Br, CH3, C2H5, NO2, OCH31 0C2H5, CF31 C2F5 or else can
carry an annelated methanediylbisoxy or ethane-1,2-
diylbisoxy group, and in addition in a 5-membered
cycloalkyl ring, a ring member can be an N or an 0, and
in a 6-membered cycloalkyl ring, one or two ring
members can be N and/or 0, whereby ring nitrogens
optionally can be substituted with C1.3 alkyl or C1.3
alkanoyl.
Also preferred is the use of compounds of general formula
CA 02396227 2002-07-04
38
II, whereby
R5 and R5' independently of one another, can be C1-6 alkyl,
whereby a carbon atom can be exchanged for 0, NH, N C1-3
alkyl, N C1-3 alkanoyl,
C3-7 cycloalkyl-C0-3 alkyl, whereby in a 5-membered
cycloalkyl ring, a ring member can be an N or an 0, and
in a 6- or 7-membered cycloalkyl ring, one or two ring
members can be N and/or 0, whereby ring nitrogens
optionally can be substituted with C1.3 alkyl or C1.3
alkanoyl, whereby the above-mentioned C1.6 alkyl part
can be substituted with one of the previously mentioned
cycloalkyls or else a 5- to 6-membered heteroaromatic
compound with 1-2 heteroatoms, selected from the group
that consists of N, S or 0,
whereby all previously mentioned alkyl and cycloalkyl
parts can be substituted with up to two substituents
that consist of CF3. OH, 0 C1-3 alkyl, and the
previously mentioned heteroaryl groups can be
substituted with one or two substituents that-consist
of F, Cl, CF3, CH3, C2H5, OCH31 OC2H5,
or R5 and R5' together with the nitrogen atom form a 5-
to 7-membered heterocyclic compound, which can contain
another oxygen, nitrogen or sulfur atom and can be
substituted with C1-4-alkyl, C1-4-alkoxy-C0-2 alkyl, C1.4-
alkoxy-carbonyl, aminocarbonyl or phenyl.
Also preferred is the use of compounds of general formula
CA 02396227 2002-07-04
39
II, whereby
A means C1.10 alkanediyl, C2_10 alkenediyl, C2.10 alkinediyl,
(C0_5 alkanediyl-C3_7 cycloalkanediyl-C0.5 alkanediyl) , or
(C0.5 alkanediyl-heteroarylene-C0.5 alkanediyl), whereby
an optionally present heteroaryl group can be
substituted with one or two substituents that consist
of F, Cl, Br, CH3, C2H5, NO2, OCH3, OC2H5, CF3. C2F5, and
in addition in a 5-membered cycloalkyl ring, a ring
member can be an N or an 0, and in a 6- or 7-membered
cycloalkyl ring, one or two ring members can be .N
and/or 0, whereby ring nitrogens optionally can be
substituted with C1_3 alkyl or C1_3 alkanoyl,
whereby in an aliphatic chain, a carbon atom or two
carbon atoms can be exchanged for 0, NH, N C1_3 alkyl,'N
C1_3 alkanoyl, NSO2 C1_3 alkyl,
and whereby alkyl or cycloalkyl parts can be
substituted with.up to two F atoms or one of the
substituents that consists of OH, 0 C1.3 alkyl, 0 C1.3
alkanoyl, =0, NH2, NH C1.3 alkyl, N (C1_3 alkyl) 2, NH C1.3
alkanoyl, N (C1.3 alkyl) (C1.3 alkanoyl) , NHCOO C1.3 alkyl,
NHCONH C1.3 alkyl, NHSO2 C1.3 alkyl, SH, S C1.3 alkyl.
Also preferred is the use of the compounds of general
formula II, whereby
B means hydrogen, OH, OCOR5 , OCONHR5 , OCOOR5 , COOH, COORS ,
CONH2 ,
CONHR5, CONR5R51, CONHOH, CONHOR5, or tetrazolyl, in each
case bonded to a carbon atom of group A.
CA 02396227 2002-07-04
40
Also preferred is the use of compounds of general formula
II, whereby
X means a bond or CH2.
Also preferred is the use of compounds of general formula
II, whereby
Y means a bond, 0, S, NH, NR4, NCOR4 or NSO2R4.
Example 307 describes how the inhibition of the microglia
activation can be measured. In this case, the activation of the
microglia can be carried out by various stimuli, such as, e.g.,
AZ-peptide (9-amyloid, Araujo, D. M.. and Cotman, C. M-. Brain Res.
569, 141-145 (1992)), prion protein, cytokines or by cell
fragments (Combs, C. K. et al. (1999) J. Neurosci., 19, 928-939,
Wood, P. L. (1998) Neuroinflammation: Mechanisms and Management,
Humana Press). For example, the compound of Example 49, 6-[[1-
(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic acid
isopropyl ester indicates an inhibition of IC50 = 0.75 m.
The stimulation with the Ai-peptide corresponds to the
pathophysiological situation in Alzheimer's disease. In this
test, the substances according to the invention showed inhibition
of microglia activation in the case of stimulation with the Ag-
peptide. The inhibition of the microglia activation by the
substances according to the invention results in a strong
reduction of the cytokine production and secretion, e.g., of 1119
and TNFa (measured by ELISA and mRNA expression analysis) and in
a reduced secretion of reactive oxygen/nitrogen intermediate
products. Several inflammation factors are thus equally
inhibited.
CA 02396227 2002-07-04
41
The in vivo action of the substances according to the
invention was shown in an MCAO model in rats. This model
simulates the state of a stroke. The substances according to the
invention reduce the microglia activation, which occurs in the
case of acute brain lesions in the brains of animals.
The invention also relates to the use of the compounds of
general formula I and of general formula II according to the
invention for the production of a pharmaceutical agent for
treating or preventing diseases that are associated with a
microglia activation. Examples of such diseases are AIDS
dementia, amyotrophic lateral sclerosis, Creutzfeldt-Jakob
disease, Down's Syndrome, diffuse Lewy Body disease, Huntington's
disease, leukoencephalopathy, multiple sclerosis, Parkinson's
disease, Pick's disease, Alzheimer's disease, stroke, temporary
,lobe epilepsy and tumors.
The invention also relates to pharmaceutical agents that
contain one or more compounds of general formula I according to
the invention and one or more vehicles. The. pharmaceutical
agents or compositions of the invention are produced in a way
that is known per se with the commonly used solid or liquid
vehicles or diluents and the commonly used pharmaceutical and
technical adjuvants corresponding to the desired type of
administration with a suitable dosage. The preferred
preparations consist of a form for dispensing that is suitable
for oral, enteral or parenteral administration. Such forms for
dispensing are, for example, tablets, film tablets, coated
tablets, pills, capsules, powders or depot forms as well as
CA 02396227 2002-07-04
42
suppositories. Corresponding tablets can be obtained, for
example, by mixing active ingredient with known adjuvants, for
example inert diluents such as dextrose, sugar, sorbitol,
mannitol, polyvinylpyrrolidone, explosives such as corn starch or
alginic acid, binders such as starch or gelatin, lubricants such
as carboxypolymethylene, carboxy methyl cellulose, cellulose
acetate phthalate or polyvinyl acetate. The tablets can also
consist of several layers.
Coated tablets can be produced accordingly by coating cores
that are produced analogously to the tablets with agents that are
commonly used in tablet coatings, for example polyvinyl
pyrrolidone or shellac, gum arabic, talc, titanium oxide or
sugar. In this case, the shell of the coated tablet can also
consist of several layers, whereby the adjuvants that are
mentioned above in the case of the tablets can be used. Capsules
that contain active ingredients can also be produced, for
example, by the active ingredient being mixed with an inert
vehicle such as lactose or sorbitol and encapsulated in gelatin
capsules.
The substances according to the invention can also be used
in suitable solutions such as, for example, physiological common
salt solution, as infusion or injection solutions.
For parenteral administration, in particular oily solutions,
such as, for example, solutions in sesame oil, castor oil and
cottonseed oil, are suitable. To increase solubility,
solubilizers can be added, such as, for example, benzyl benzoate
or benzyl alcohol.
CA 02396227 2002-07-04
43
It is also possible to incorporate the substances according
to the invention in a transdermal system and to administer them
transdermally.
The dosage of the substances of general formula I and of
general formula II according to the invention is determined by
the attending physician and depends on, i.a., the substance that
is administered, the method of administration, the disease that
is to be treated and the severity of the disease. The daily dose
is no more than 1000 mg, preferably no more than 100 mg, whereby
the dose can be given as a single dose to be administered once or
divided into 2 or more daily doses.
The compounds of formula I can be present as tautomers,
stereoisomers or geometric isomers. The invention also comprises
all possible isomers, such as E- and Z-isomers, S- and R-
enantiomers, diastereomers, racemates and mixtures thereof,
including the tautomeric compounds.
The isomer mixtures can be separated into enantiomers or E/Z
isomers according to commonly used methods, such as, for example,
crystallization, chromatography or salt formation.
The production of the compounds according to the invention
is carried out analogously to known processes that are described
in, for example, EP 531 883. If the production of the starting
compounds is not described, the starting compounds are known and
are commercially available or their production is carried out
analogously to the processes described here. Below, the
production of some precursors, intermediate products and products
is described by way of example.
CA 02396227 2002-07-04
44
In the production of the substances according to the
invention, for example, the following processes are used:
General Operating Instructions 1:
Reduction nitro groups, hydrogenation of olefinic double bonds
and hydrogenolytic cleavage of benzyl ethers
The compound that is to be reduced is dissolved in ethyl
acetate, tetrahydrofuran, methanol or ethanol or mixtures of the
solvent, and it is hydrogenated to 2-5% (relative to the nitro
compound) palladium on carbon (10%) at normal pressure. After
hydrogen absorption has ended, it is suctioned off, the residue
is washed with ethyl acetate or methanol or ethanol, and the
filtrate is concentrated by evaporation in a vacuum. The crude
product is reacted generally without further purification.
General Operating Instructions 2:
Reduction nitro groups
9.2 g of iron(II) sulfate is introduced into 30 ml of water
and 9 ml of ammonia solution. A solution that consists of 3.6
mmol of the nitro compound in 100 ml of ethanol is added in drops
to it, and the suspension is stirred intensively for 1 hour at
70 C. Then, it is allowed to settle, solid is filtered out, the
filtrate is concentrated by evaporation to a large extent, mixed
with water and extracted three times with ethyl acetate. The
combined extracts are dried on sodium sulfate and concentrated by
evaporation in a vacuum. The amino compound is further processed
as a crude product.
CA 02396227 2002-07-04
45
General Operating Instructions 3:
Cyclization to benzimidazoles with orthoesters
mmol of a 1,2-diaminobenzene derivative is dissolved in
25 ml of ethanol. 47 ml of an 0.8 M ethereal HC1 solution is
added in drops to it, it is stirred for 30 minutes and then
evaporated to the dry state in a vacuum. The residue is taken up
in 230 ml of methanol and mixed with 6 ml of trimethyl
orthobenzoate or the corresponding amount of another orthoester.
It is refluxed for 2-8 hours, poured onto saturated sodium
bicarbonate solution after cooling, extracted three times with
ethyl acetate, the combined extracts are dried on sodium sulfate
and concentrated by evaporation in a vacuum. The residue is
purified by crystallization or column chromatography on silica
gel.
General Operating Instructions 4:
Cyclization to benzimidazoles with imino ester hydrochlorides
1.2 mmol of a 1,2-diaminobenzene derivative is dissolved in
5 ml of tetrahydrofuran, mixed with 1.5 mmol of a benzimidate
hydrochloride, and the mixture is stirred for 15 hours. The
batch is mixed with saturated sodium bicarbonate solution,
diluted with water and extracted three times with ethyl acetate.
The combined organic phases are washed three times with IN
aqueous hydrochloric acid and once with saturated sodium chloride
solution, dried on sodium sulfate, filtered on a frit with silica
CA 02396227 2002-07-04
46
gel, and the solution is evaporated to the dry state. The
product crystallizes from diisopropyl ether.
General Operating Instructions 5:
Cyclization to benzimidazoles via carboxylic acid anilides
4.7 mmol of a 1,2-diaminobenzene derivative is dissolved in
20 ml of dichloromethane, mixed with 14 mmol of triethylamine and
mixed slowly with 6 mmol of carboxylic acid chloride, and the
mixture is stirred for 15 hours. The batch is mixed with
saturated sodium bicarbonate solution, diluted with water and
extracted twice with dichloromethane. The combined organic
phases are washed with water and with saturated sodium chloride
solution, dried on sodium sulfate and concentrated by evaporation
in a vacuum. The remaining crude carboxylic acid anilide is
taken up in a 9:1 mixture that consists of methanol and
concentrated hydrochloric acid and refluxed for 1 hour. The
reaction mixture is slowly introduced into saturated sodium
bicarbonate solution after cooling, diluted with water and
extracted three times with dichloromethane. The combined organic
phases are washed with saturated sodium chloride solution, dried
on sodium sulfate and concentrated by evaporation in a vacuum.
The residue is purified, if necessary, by crystallization or
column chromatography on silica gel.
CA 02396227 2002-07-04
47
General Operating Instructions 6:
Ether cleavage with hydrobromic acid
g of aryl methyl ether is mixed with 160 ml of 48% aqueous
HBr and refluxed for 1-5 hours. After cooling, it is filtered.
The residue is taken up in ethyl acetate, and it is extracted
three times with saturated sodium bicarbonate solution. After
drying on sodium sulfate, it is concentrated by evaporation in a
vacuum. The residue is purified, if necessary, by
crystallization or column chromatography on silica gel.
General Operating Instructions 7:
Ether cleavage with boron tribromide
1.86 mmol of aryl methyl ether is dissolved in 18 ml of
dichloromethane and mixed slowly at -35 C with 7.4 ml of a 1 M
solution of boron tribromide in dichloromethane. It is left for
12-15 hours at -30 C, then mixed with saturated sodium
bicarbonate solution, extracted three times with dichloromethane,
the combined extracts are dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue is
purified, if necessary, by column chromatography on silica gel.
General Operating Instructions 8:
Akylation of hydroxybenzimidazole derivatives and phenol
derivatives with alkyl halides
A solution of 1.85 mmol of the hydroxybenzimidazole
derivative in 12 ml of N,N-dimethylformamide is mixed with 1.85
mmol of cesium carbonate, and 2.24 mmol of alkyl bromide or alkyl
CA 02396227 2002-07-04
48
iodide. When alkyl bromides are used, optionally 1.85 mmol of
sodium iodide is added. It is stirred for 12-96 hours, then
poured onto water, taken up with ethyl acetate, the organic phase
is washed four times with water, dried on sodium sulfate and
concentrated by evaporation in a vacuum.
As an alternative to this aqueous working up, the reaction
mixture can be mixed with dichloromethane, separated from the
precipitating salts by filtration and the filtrate concentrated
by evaporation in a vacuum.
Independently of the working-up method, the residue is
purified by crystallization or column chromatography on silica
gel.
General Operating Instructions 9:
Saponification of carboxylic acid alkyl esters
0.77 mmol of the carboxylic acid alkyl ester is dissolved in
ml of methanol and 5 ml of tetrahydrofuran, and it is mixed
with 5 ml of a 0.5N aqueous lithium or sodium hydroxide solution.
After 2-12 hours of stirring, it is concentrated by evaporation
in a vacuum to a very large extent, neutralized by the addition
of aqueous hydrochloric acid and extracted with ethyl acetate.
It is dried on sodium sulfate and concentrated by evaporation in
a vacuum. The residue is purified, if necessary, by column
chromatography on silica gel.
CA 02396227 2002-07-04
49
General Operating Instructions 10:
Esterification of carboxylic acids
0.2 mmol of carboxylic acid is dissolved in 1 ml of primary
or secondary alcohol, mixed with two drops of concentrated
sulfuric acid and stirred for 12 hours at 60 C. The batch is
then mixed with saturated potassium bicarbonate solution, diluted
with water and extracted three times with ethyl acetate. After
the combined extracts are washed with saturated sodium chloride
solution and dried on sodium sulfate, it is concentrated by
evaporation in a vacuum, and the residue is crystallized from
diisopropyl ether.
General Operating Instructions 11:
Reduction of carboxylic acid alkyl esters with lithium aluminum
hydride
0.15 mmol of carboxylic acid ester is dissolved in
tetrahydrofuran and mixed with 0.09 mmol of lithium aluminum
hydride. It is allowed to stir for 1-48 hours, mixed with water
and extracted three times with dichloromethane. After the
combined organic phases are dried on sodium sulfate, it is
concentrated by evaporation in a vacuum. The residue is
purified, if necessary, by crystallization or by column
chromatography on silica gel.
CA 02396227 2002-07-04
CA 02396227 2002-07-04
General Operating Instructions 12:
Wittig reaction of benzimidazole carbaldehydes with (w-carboxy-
alkyl)triphenylphosphonium bromides and esterification with
methanol
2 mmol of the (w-carboxyalkyl)triphenylphosphonium bromide
is mixed in 2.5 ml of dimethyl sulfoxide and 2.5 ml of
tetrahydrofuran at 0 C with 4 mmol of potassium-tert-butylate,
and it is stirred for 30 minutes at T > 10 C. Then, a solution
that consists of 0.67 mmol of the aldehyde in 2 ml of
tetrahydrofuran is added, and it is stirred for 3 hours at 20 C.
The batch is then mixed with saturated ammonium chloride
solution, diluted with water and extracted three times with ethyl
acetate. After the combined organic phases are dried on sodium
sulfate, it is concentrated by evaporation in a vacuum. The
residue is dissolved in 15 ml of methanol, mixed with two drops
of concentrated sulfuric acid and allowed to stand for 48-72
hours. After concentration by evaporation in a vacuum, the
residue is purified by column chromatography on silica gel.
General Operating Instructions 13:
Reaction of aminobenzimidazoles with alkyl- and arylsulfonic acid
halides
47 mol of aminobenzimidazole derivative is dissolved in 0.5
ml of dichloromethane, mixed with 51 mol of triethylamine and 51
mol of alkyl- or arylsulfonic acid halide, and the reaction
mixture is stirred for 2-15 hours. For working-up, saturated
sodium bicarbonate solution is added, extracted three times with
51
dichloromethane, the combined organic phases are washed with
water, dried on sodium sulfate and concentrated by evaporation in
a vacuum. The residue is purified by crystallization or by
column chromatography on silica gel.
General Operating Instructions 14:
Copper-mediated 0- or N-arylation of benzimidazoles
mmol of an N-unsubstituted benzimidazole derivative or an
N-aryl-substituted hydroxybenzimidazole derivative is dissolved
in 20 ml of dichloromethane. 10.mmol of an arylboronic acid, 5
mmol of anhydrous copper(II) acetate, 10 mmol of pyridine or
triethylamine and about 2.5 g of molecular sieve (4) are added,
stirred for 48-72 hours in a moisture-free environment, then
silica gel is added, it is evaporated to the dry state in a
vacuum, and the remaining powder is purified by chromatography on
silica gel. Regioisomeric N-arylation products are separated, if
necessary, using HPLC.
General Operating Instructions 15:
Base-catalyzed_N-substitution of benzimidazoles
5 mmol of an N-unsubstituted benzimidazole derivative is
dissolved in 20 ml of dimethylacetamide. 25 mmol of sodium
hydride and 20 mmol of an electron-free aryl or heteroaryl halide
are added and refluxed for 48-72 hours in a moisture-free
environment, then silica gel is added, it is evaporated to the
dry state in a vacuum, and the remaining powder is purified by
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52
chromatography on silica gel. Regioisomeric N-arylation products
are separated, if necessary, using HPLC.
General Operating Instructions 16:
Cyclization to benzimidazoles with aldehydes
1 mmol of a 1,2-diaminobenzene derivative is dissolved in 3
ml of nitrobenzene. 1 mmol of an aryl- or heteroaryl aldehyde is
added to this. It is heated for 2-6 hours to 150 C and allowed
to cool. The residue is directly purified by column
chromatography on silica gel without further working-up.
General Operating Instructions 17:
Cqnversion of carboxylic acids into carboxylic acid amides
0.25 mmol of a carboxylic acid is dissolved in 3 ml of N,N-
dimethylformamide, mixed with 0.38 mmol of a primary or secondary
amine, 0.5 mmol of triethylamine and 0.25 mmol of
diphenylphosphorylazide, and the mixture is stirred for 2 days.
For working-up, water is added, it is extracted three times with
ethyl acetate, the combined organic phases are washed with water,
dried on sodium sulfate and concentrated by evaporation in a
vacuum. The residue is purified by column chromatography on
silica gel.
General Operating Instructions 18:
Conversion of carboxylic acid esters into carboxylic acid amides
0.36 mmol of an amine is dissolved in 3 ml of toluene and
mixed drop by drop with 0.18 ml of a 2 M solution of
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53
trimethylaluminum in toluene while being cooled in an ice bath.
It is mixed with a solution that consists of 0.33 mmol of the
carboxylic acid methyl ester in 3 ml of toluene and stirred for
2-8 hours at 95 C. For working-up, water is added after cooling,
it is extracted three times with ethyl acetate, the combined
organic phases are washed with saturated sodium chloride
solution, dried on sodium sulfate and concentrated by evaporation
in a vacuum. The residue is purified by column chromatography on
silica gel.
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Example 1
[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]acetic acid isopropyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole (Benincori, T.; Sannicolo, F.; J. Heterocycl.
Chem.; 25; 1988; 1029-1033) with bromoacetic acid isopropyl ester
according to general operating instructions 8.
Flash point 137-138 C
Example 2
[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]ethan-l-ol
was obtained by reaction of [(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]acetic acid methyl ester (DE 4330959) according to general
operating instructions 11.
'H-NMR (D6-DMSO): 6 = 3.72 ppm t (J = 7.5 Hz, 2H); 4.02 t
(J = 7.5 Hz, 2H); 6.72 d (J = 2 Hz, 1H); 7.10 dd (J = 8, 2 Hz,
1H); 7.38-7.68 m (10H); 7.76 d (J = 8 Hz, 1H).
Example 3
3-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]propan-l-ol
0.5 g of 1,2-diphenyl-6-hydroxy-lH-benzimidazole was reacted
according to general operating instructions 8 with 3-
(bromopropoxy)-tert-butyldimethylsilane. After chromatography on
silica gel, it was taken up in 2.5 ml of methanol, 0.4 ml of
concentrated hydrochloric acid was added, and it was allowed to
stir for 2 hours at 20 C. It was poured onto saturated aqueous
sodium bicarbonate solution, extracted three times with ethyl
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acetate, the combined extracts were washed with saturated aqueous
sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum.
Flash point 191-193 C
Example 4
3-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid
100 mg of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propan-
1-01 was introduced into 2.5 ml of acetone and mixed at -15 C
with 0.15 ml of a solution of Jones reagent (produced from 0.27 g
of chromium(VI) oxide, 1 ml of water and 0.23 ml of concentrated
sulfuric acid). After 3.5 hours of stirring at -15 C, it was
quenched with the addition of isopropanol. It was diluted with
water, extracted three times with dichloromethane, the combined
organic phases were dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue was purified by
chromatography on silica gel.
'H-NMR (D6-DMSO): 6 = 2.60 ppm t (J = 7.5 Hz, 2H), 4.15 t
(J = 7.5 HZ, 2H); 6.64 d (J = 2 Hz, 1H); 6.95 dd (J = 8, 2 Hz,
1H); 7.30-7.61 m (10H); 7.69 d (J = 8 Hz, 1H).
Example 5
3-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid methyl
ester
45 mg of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic
acid was dissolved in 0.5 ml of N,N-dimethylformamide and mixed
with 41 mg of cesium carbonate and 10 Al of methyl iodide. It
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56
was allowed to stir for 2 days, diluted with dichloromethane,
filtered, the filtrate was concentrated by evaporation in a
vacuum, and the residue was chromatographed on silica gel.
Flash point 120-121 C
Example 6
2-[(1,2-Diphenyl-iH-benzimidazol-6-yl)oxy]propanoic acid methyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-1H-
benzimidazole with 2-brornopropanoic acid methyl ester according
to general operating instructions 8.
Flash point 132-135 C
Example 7
4-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]butanoic acid isopropyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-1H-
benzimidazole with 4-bromobutanoic acid isopropyl ester according
to general operating instructions 8.
Flash point 89-91 C
Example 8
4-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]butan-l-ol
was obtained by reaction of 4-[(1,2-diphenyl-lH-benzimidazol-6-
yl)oxy]butanoic acid methyl ester according to general operating
instructions 11.
Flash point 159-160 C
57
Example 9
Acetic acid-[4-((1,2-diphenyl-1H-benzimidazol-6-yl)oxy]but-1-
yl] ester
50 mg of 4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butan-l-
ol was dissolved in 1 ml of dichloromethane, mixed with 0.34 ml
of pyridine and 20 Al of acetyl chloride and stirred for 15
hours. It was mixed with saturated sodium bicarbonate solution,
diluted with water, extracted twice with dichloromethane, the
combined organic phases were washed with saturated sodium
chloride solution, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue was purified using thick-
layer chromatography.
Flash point 68-69 C
Example 10
Pivalic acid-[4-((1,2-diphenyl-lH-benzimidazol-6-yl)oxy]but-1-
yl] -ester
was produced analogously to the instructions, indicated in
Example 9, from 50 mg of 4-((1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]butan-l-ol, 0.34 ml of pyridine and 22 Al of
trimethylacetic acid chloride.
Flash point 104-106 C
Example 11
4-((1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]butyl-N-methylcarbamate
100 mg of 4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butan-l-
ol was dissolved in 4 ml of dichloromethane, mixed with 0.1 ml of
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58
triethylamine and 20 mg of methyl isocyanate and stirred for 15
hours. Another 0.1 ml of triethylamine and 20 mg of methyl
isocyanate were added, allowed to stir for 20 hours, and then
concentrated by evaporation in a vacuum. The residue was
purified using chromatography on silica gel.
Flash point 124-126 C
Example 12
5-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]pentanoic acid
isopropyl ester 994
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 5-bromopentanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 91-92 C
Example 13
6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]hexanoic acid methyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
1H-NMR (CDC13) 6 = 1.44-1.56 m (2H) ; 1.64-1.85 m (4H)
2.33 t (J = 7.5 Hz, 2H); 3.66 s (3H); 3.93 t (J = 7.5 Hz, 2H);
6.70 d (J = 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H); 7.22-7.38 m
(5H); 7.43-7.58 m (5H); 7.76 d (J = 8 Hz, 1H).
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59
Example 14
6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]hexanoic acid isopropyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 6-bromohexanoic acid isopropyl ester according
to general operating instructions 8.
1H-NMR (CDC13): 6 = 1.22 ppm d (J = 7.5 Hz, 6H); 1.43-1.56
m (2H); 1.62-1.87 m (4H); 2.30 t (J = 7.5 Hz, 2H); 3.93 t (J =
7.5 Hz, 2H); 5.01 sp (J = 7.5 Hz, 1H); 6.69 d (J = 2 Hz, 1H);
6.96 dd (J = 8, 2 Hz, 1H); 7.25-7.38 m (5H); 7.43-7.55 m (5H);
7.75 d (J = 8 Hz, 1H).
Example 15
6-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid
was obtained by reaction of 6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester according to general operating
instructions 9.
'H-NMR (D6-DMSO) 6 = 1.35-1.49 ppm m (2H) ; 1.50-1.63 m
(2H); 1.65-1.77 m (2H); 2.23 t (J = 7.5 Hz, 2H); 3.92 t (J = 7.5
Hz, 2H); 6.62 d (J = 2 Hz, 1H); 6.95 dd (J = 10, 2 Hz, 1H); 7.30-
7.62 m (10H) ; 7.68 d (J = 10 Hz, 1H)
Example 16
6-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]hexan-l-ol
was obtained by reaction of 6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester according to general operating
instructions 11.
60
'H-NMR (CDC13): 6 = 1.35-1.85 ppm m (8H); 3.67 t (J = 7.5
Hz, 2H); 3.98 t (J = 7.5 Hz, 2H); 6.70 d (J = 2 Hz, 1H); 6.98 dd
(J = 8.2 Hz, 1H); 7.24-7.38 m (5H); 7.45-7.58 m (5H); 7.75 d (J =
8 Hz, 1H).
Example 17
6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
a) 6-[(1,2-Diphenyl-3.H-benzimidazol-6-yl)oxy]hexanonitrile
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 6-bromohexanonitrile according to general
operating instructions 8.
Flash point 108-112 C
6-[(1,2-Diphenyl-3.H-benzimidazol-6-yl)oxy]hexanamide
18 mg of potassium carbonate and 40 Al of 30% hydrogen
peroxide solution were added to a solution that consists of 50 mg
of 6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanonitrile in 1
ml of methanol, and it was allowed to stir for 24 hours. Then,
ice-cold aqueous sodium thiosulfate solution was stirred in and
extracted three times with ethyl acetate. After drying on sodium
sulfate, it was concentrated by evaporation in avacuum, and the
residue was chromatographed on silica gel.
1H-NMR (CDC13) : 6 = 1.48-1.60 ppm m (2H) ; 1.65-1.87 m (4H) ;
2.25 t (J = 7.5 Hz, 2H); 3.94 t (J = 7.5 Hz, 2H); 5.30-5.53 broad
(2H), 6.68 d (J = 2 Hz, 1H); 6.95 dd (J = 8, 2 Hz, 1H); 7.23-7.38
m (5H); 7.42-7.58 m (5H), 7.75 d (J = 8 Hz, 1H).
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61
Example 18
N-Methoxy-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide
100 mg of 6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanoic
acid was dissolved in 2 ml of tetrahydrofuran, mixed with 39 mg
of carbonyldiimidazole, stirred for 30 minutes at 20 C and then
refluxed for 30 minutes. At 20 C, 21 mg of O-
methylhydroxyaminohydrochloride was then added, and it was
allowed to stir for 18 hours. The reaction mixture was diluted
with ethyl acetate and washed with 2N aqueous hydrochloric acid
and saturated potassium bicarbonate solution. After drying on
sodium sulfate, it was concentrated by evaporation in a vacuum,
and the residue was chromatographed on silica gel.
Flash point 144-145 C
Example 19
N-(Phenylmethoxy)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl) oxy] hexanamide
was obtained by reaction of 6-((1,2-diphenyl-lH-benzimidazol-6-
yl)oxy]hexanoic acid with O-benzylhydroxylaminohydrochloride
according to the general operating instructions that are
indicated in Example 18.
Flash point 144 C
62
Example 20
N-Hydroxy-6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
23 mg of N-(phenylmethoxy)-6-[(1,2-diphenyl-lH-benzimidazol-
6-yl)oxy]hexanamide was dissolved in 4 ml of ethanol, mixed with
15 mg of palladium on carbon (10%) and stirred under a hydrogen
atmosphere for 3 hours. After catalyst was separated out, it was
concentrated by evaporation in a vacuum, and the residue was
crystallized from diethyl ether.
Flash point 83-85 C
Example 21
7-[(1,2-Diphenyl-iH-benzimidazol-6-yl)oxy]heptanoic acid methyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 7-bromoheptanoic acid methyl ester according
to general operating instructions 8.
Flash point 77-80 C
Example 22
7-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]heptanoic acid
was obtained by reaction of 7-[(1,2-diphenyl-lH-benzimidazol-6-
yl)oxy]heptanoic acid methyl ester according to general operating
instructions 9.
Flash point 142-145 C
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63
Example 23
7-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]heptanoic acid
isopropyl ester
was obtained by reaction of 7-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]heptanoic acid with isopropanol according to general
operating instructions 10.
Flash point 98-100 C
Example 24
6-[[1-(3-Nitrophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-l-(3-nitrophenyl)-2-phenyl-
1H-benzimidazole (DE 4330959) with 6-bromohexanoic acid isopropyl
ester according to general operating instructions 8.
Flash point 111-113 C
Example 25
6-[[2-Phenyl-l-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) (5-Methoxy-2-nitrophenyl)[(3-trifluoromethyl)phenyl]amine
2 g of 3-fluoro-4-nitroanisole and 16 ml of 3-
(trifluoromethyl) aniline were stirred for 72 hours at 140 C. The
batch was then.diluted with ethyl acetate, washed ten times with
4N aqueous hydrochloric acid and once with saturated sodium
chloride solution, dried on sodium sulfate, concentrated by
evaporation in a vacuum, and the residue was chromatographed on
silica gel.
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64
'H-NMR (CDC13) : S = 3.78 ppm s (3H) ; 6.42 dd (J = 8, 2 Hz,
1H); 6.60 d (J = 2 Hz, 1H); 7.45-7.60 m (4H); 8.22 d (J = 8 Hz,
1H) ; 9.78 s (broad) (1H) .
b) 6-Methoxy-2-phenyl-l-[(3-trifluoromethyl)phenyl]-1H-
benzimidazole
was obtained by hydrogenation of (5-methoxy-2-nitrophenyl)[(3-
trifluoromethyl)phenyl] amine according to general operating
instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
Flash point 135-137 C
c) 6-Hydroxy-2-phenyl-1-[(3-trifluoromethyl)phenyl]-.1H-
benzimidazole
was obtained by reaction of 6-methoxy-2-phenyl-l-[(3-
trifluoromethyl)phenyl]-1H-benzimidazole according to general
operating instructions 6.
1H-NMR (D6-DMSO) : 6 = 6.56 ppm d (J = 2 Hz, 1H); 6.82 dd (J
= 8, 2 Hz, 1H); 7.32-7.50 m (5H); 7.60 d (J = 8 Hz, 1H); 7.70-
7.95 m (4H) ; 9.48 s (broad) (1H) .
6-[[2-Phenyl-l-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-hydroxy-2-phenyl-l-[(3-
trifluoromethyl)phenyl]-1H-benzimidazole with 6-bromohexanoic
acid methyl ester according to general operating instructions 8.
Flash point 106-108 C
65
Example 26
6-[[2-Phenyl-l-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid-isopropylester
was obtained by reaction of 6-hydroxy-2-phenyl-l-[(3-
trifluoromethyl)phenyl]-1H-benzimidazole with 6-bromohexanoic
acid isopropyl ester according to general operating instructions
8.
Flash point 113-115 C
Example 27
6-[[2-Phenyl-l-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[2-phenyl-l-[3-
(trifluoromethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester according to general operating instructions 9.
Flash point 156-158 C
Example 28
6- [ [2-Phenyl-l- [3- (trifluoromethyl)phenyl] -1H-benzimidazol-6-
yl] oxy] hexan- l-ol
was obtained by reaction of 6-[[2-phenyl-l-[3-
(trifluoromethyl)phenyl]-lH-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester according to general operating instructions 11.
Flash point 143-145 C
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66
Example 29
6-[[1-(3-Cyanophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 3-(5-Methoxy-2-nitrophenyl)aminobenzonitrile
2 g of 3-fluoro-4-nitroanisole and 15 ml of 3-
aminobenzonitrile were stirred for 65 hours at 140 C. The batch
was then diluted with ethyl acetate, washed three times with
water and once with saturated sodium chloride solution, dried on
.sodium sulfate, concentrated by evaporation in a vacuum, and the
residue was chromatographed on silica gel.
Flash point 157-158 C
b) 6-Methoxyl-(3-cyanophenyl)-2-phenyl-lH-benzimidazole
was obtained by hydrogenation of 3-(5-methoxy-2-
nitrophenyl)aminobenzonitrile according to general operating
instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3. In
the cyclization, tetrahydrofuran, contrary to the general
operating instructions, was.used as a solvent.
Flash point 185-191 C (decomposition)
c) 6-Hydroxy-l-(3-cyanophenyl)-2-phenyl-lH-benzimidazole
was obtained by reaction of 6-methoxyl-(3-cyanophenyl)-2-phenyl-
1H-benzimidazole according to general operating instructions 7.
Flash point 216-218 C
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67
6-[[1-(3-Cyanophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-hydroxy-l-(3-cyanophenyl)-2-phenyl-
1H-benzimidazole with 6-bromohexanoic acid methyl ester according
to general operating instructions 8.
Flash point 115-118 C
Example 30
6-[[1-(3-Cyanophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-l-(3-cyanophenyl)-2-phenyl-
1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 101-102 C
Example 31
6-[[1-(3-Cyanophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[1-(3-cyanophenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 99-101 C
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68
Example 32
6-[[1-(4-Cyanophenyl)-2-phenyl-iH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 4-(5-Methoxy-2-nitrophenyl)aminobenzonitrile
2 g of 3-fluoro-4-nitroanisole and 15 ml of 4-
aminobenzonitrile were stirred for 22 hours at 140 C. The batch
was then diluted with ethyl acetate, washed three times with 2N
aqueous hydrochloric acid, three times with water and once with
saturated sodium chloride solution, dried on sodium sulfate,
concentrated by evaporation in a vacuum, and the residue was
chromatographed on silica gel.
'H-NMR (CDC13) : 6 = 3.70 ppm s (3H) ; 6.38 dd (J = 8, 2 Hz,
1H); 6.68 d (J = 2 Hz, 1H); 7.27 d (J = 8 Hz, 2H); 7.54 d (J = 8
Hz, 2H); 8.08 d (J = 8 Hz, 1H); 9.60 s (broad)(1H).
b) 6-Methoxyl-(4-cyanophenyl)-2-phenyl-lH-benzimidazole
was obtained by hydrogenation of 4-(5-methoxy-2-
nitrophenyl)aminobenzonitrile according to general operating
instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to. general operating instructions 3. In
the cyclization, tetrahydrofuran, contrary to the general
operating instructions, was used as a solvent.
1H-NMR (CDC13) 6 = 3.82 ppm s (3H) ; 6.72 d (J = 2 Hz, 1H);
7.00 dd (J = 8.2 Hz, 1H); 7.30-7.49 m_(7H); 7.78 d (J = 8 Hz,
1H) ; 7.81 d (J = 8 Hz, 2H) .
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c) 6-Hydroxy-l-(4-cyanophenyl)-2-phenyl-1H-benzimidazole
was obtained by reaction of 6-methoxy-l-(4-cyanophenyl)-2-phenyl-
1H-benzimidazole according to general operating instructions 7.
Flash point 266-268 C
6-[[1-(4-Cyanophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-hydroxy-l-(4-cyanophenyl)-2-phenyl-
1H-benzimidazole with 6-bromohexanoic acid methyl ester according
to general operating instructions S.
Flash point 145-148 C
Example 33
6-[[1-(4-Cyanophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-l-(4-cyanophenyl)-2-phenyl-
1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 102-103 C
Example 34
6-[[1-(3-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 1-(3-Chlorophenyl)-6-methoxy-2-phenyl-1H-benzimidazole
was obtained by reduction of (3-chlorophenyl)-(5-methoxy-2-
nitrophenyl)amine (Belton, McInerney; Proc. R. Ir. Acad. Sect. B:
69; 1970; 21,27) according to general operating instructions 2
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and subsequent cyclization with triethyl orthobenzoate according
to general operating instructions 3.
Flash point 140-143 C
b) 1-(3-Chlorophenyl)-6-hydroxy-2-phenyl-1H-benzimidazole
was obtained by reaction of 6-methoxy-l-(3-chlorophenyl)-2-
phenyl-1H-benzimidazole according to general operating
instructions 6.
Flash point 210-214 C
6-[[1-3-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 1-(3-chlorophenyl)-6-hydroxy-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 101-105 C
Example 35
6-[[1-(3-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 1-(3-chlorophenyl)-6-hydroxy-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 107-112 C
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Example 36
6-[[1-(3-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[1-(3-chlorophenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
1H-NMR (D6-DMSO) : 6 = 1.36-1.78 ppm m (6H); 2.24 t (J = 7.5
Hz, 2H); 3.96 t (J = 7.5 Hz, 2H); 6.68 d (J = 2 Hz, 1H); 6.97 dd
(J = 8, 2 Hz, 1H); 7.32-7.65 m (9H); 7.69 d (J = 8 Hz, 1H).
Example 37
6-[[1-(3-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexan-l-
ol
was obtained by reaction of 6-[[1-(3-chlorophenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
1H-NMR (CDC13): 6 = 1.38-1.88 ppm m (8H); 3.67 t (J = 7.5
Hz, 2H); 3.96 t (J = 7.5 Hz, 2H); 6.70 d (J = 2 Hz, 1H); 6.97 dd
(J = 8, 2 Hz, 1H); 7.18 ddd (J = 8, 2, 2 Hz, 1H); 7.25-7.55 m
(8H); 7.76 d (J = 8 Hz, 1H).
Example 38
6-[[1-(4-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 1-(4-Chlorophenyl)-6-methoxy-2-phenyl-lH-benzimidazole
was obtained by reduction of (4-chlorophenyl)-(5-methoxy-2-
nitrophenyl)amine (Kottenhahn et al., J. Org. Chem.; 28; 1963;
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3114, 3118) according to general operating instructions 2 and
subsequent cyclization with triethyl orthobenzoate according to
general operating instructions 3.
1H-NMR (CDC13) : 6 = 3.82 ppm s (3H); 6.67 d (J = 2 Hz, 1H);
6.97 dd (J = 8, 2 Hz, 1H); 7.22-7.40 m (5H); 7.46-7.55 m (4H);
7.77 d (J = 8 Hz, 1H).
b) 1-(4-Chlorophenyl)-6-hydroxy-2-phenyl-1H-benzimidazole
was obtained by reaction of 6-methoxy-l-(4-chlorophenyl)-2-
phenyl-1H-benzimidazole according to general operating
instructions 6.
1H-NMR (D6-DMSO): 6 = 6.60 ppm d (J = 2 Hz, 1H); 6.87 dd (J
8, 2 Hz, 1H); 7.40-7.56 m (7H); 7.64 d (J = 8 Hz, 1H); 7.70 d
(J = 8 Hz, 2H); 9.50 s (broad)(1H).
6-[[1-(4-Chlorophenyl)-2-phenyl-iH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 1-(4-chlorophenyl)-6-hydroxy-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 100-104 C
73
Example 39
6-[[1-(4-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 1-(4-chlorophenyl)-6-hydroxy-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 83-88 C
Example 40
6-[[1-(4-Chlorophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy].hexanoic
acid
was obtained by reaction of 6-[[1-(4-chlorophenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
1H-NMR (D6-DMSO): 6 = 1.35-1.78 ppm m (6H); 2.25 t (J = 7.5
Hz, 2H); 3.94 t (J = 7.5 Hz, 2H); 6.68 d (J = 2 Hz, 1H); 6.95 dd
(J = 8, 2 Hz, 1H); 7.33-7.54 m (7H); 7.63 d (J = 8 Hz, 2H); 7.69
d (J = 8 Hz, 1H).
Example 41
6-[[1-(4-Chlorophenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexan-l-
ol
was obtained by reaction of 6-[[].-(4-chlorophenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
Flash point 115-120 C
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Example 42
6-[[1-(2-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 5-Chloro-2-nitrophenyl-o-tolylamine
81 ml of o-toluidine was added to a solution that consists
of 10 g of 1-chloro-3,4-dinitrobenzene in 50 ml of ethanol, and
it was refluxed for 72 hours. It was concentrated by evaporation
in a vacuum, and the residue was taken up in ethyl acetate and 2N
aqueous hydrochloric acid. The organic phase was extracted three
more times with 2N aqueous hydrochloric acid, dried on sodium
sulfate and concentrated by evaporation in a vacuum. The residue
was purified by chromatography on silica gel.
'H-NMR (CDC13) 2.28 ppm s (3H); 6.70 dd (J = 10, 2 Hz,
1H); 6.80 d (J = 2 Hz, 1H); 7.22-7.40 m (4H); 8.18 d (J = 10 Hz,
1H) ; 9.40 s (broad) (1H) .
b) 5-Methoxy-2-nitrophenyl-o-tolylamine
1 g of 5-chloro-2-nitrophenyl-o-tolylamine was added to a
solution that consists of 1 g of sodium in 20 ml of methanol, and
it was refluxed for 72 hours. Then, it is cooled to 0 C, and the
crystalline product is suctioned off.
'H-NMR (CDC13) : 6 = 2.30 ppm s (3H) ; 3.72 s (3H) ; 6.19 d (J
= 2 Hz, 1H); 6.32 dd (J = 10, 2 Hz, 1H); 7.20-7.40 m (4H); 8.20 d
(J = 10 Hz, 1H) ; 9.62 s (broad) (1H) .
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c) 6-Methoxy-l-(2-methylphenyl)-2-phenyl-3-H-benzimidazole
was obtained by reaction of 5-methoxy-2-nitrophenyl-o-tolylamine
according to general operating instructions 1 and subsequent
cyclization with triethyl orthobenzoate according to general
operating instructions 3.
1H-NMR (CDC13) : 6 = 1.93 ppm s (3H) ; 3.78 S (3H) ; 6.42 d (J
2 Hz, 1H); 6.97 dd (J = 8, 2 Hz, 1H); 7.22-7.48 m (7H); 7.57 dd
(J = 8, 1 Hz, 2H) ; 7.78 d (J = 8 Hz, 1H).
6-[[1-(2-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
6-Methoxy-l-(2-methylphenyl)-2-phenyl-lH-benzimidazole was
reacted according to general operating instructions 6. The crude
product was reacted with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.43-1.58 ppm m (2H) ; 1.62-1.84 m (4H);
1.93 s (3H); 2.34 t (J = 7.5 Hz, 2H); 3.68 s (3H); 3.90 t (J =
7.5 Hz, 2H); 6.42 d (J = 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H);
7.22-7.48 m (7H); 7.56 dd. (J = 8, 1.5 Hz, 2H); 7.76 d (J = 8 Hz,
1H) .
Example 43
6-[[1-(2-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[1-(2-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
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Flash point 198-200 C
Example 44
6-[[1-(3-Methylphenyl)-2-phenyl-iH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 5-Chloro-2-nitrophenyl-m-tolylamine
81 ml of m-toluidine is added to a solution that consists of
50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol, and the
solution was allowed to stand for 72 hours. The reaction mixture
was filtered, and the crystallizate was washed with cold ethanol
and 2N aqueous hydrochloric acid. It was purified by
chromatography on silica gel.
'H-NMR (CDC13) : 6 = 2.40 ppm s (3H) ; 6.72 dd (J = 10, 2 Hz,
1H); 7.04-7.13 m (3H); 7.14 d (J = 2 Hz, 1H), 7.32 t (J = 10 Hz,
1H); 8.18 d (J = 10 Hz, 1H); 9.52 s (broad)(1H).
b) 5-Methoxy-2-nitrophenyl-m-tolylamine
39 g of 5-chloro-2-nitrophenyl-m-tolylamine was added to a
solution that consists of 9 g of sodium in 670 ml of methanol,
and it was refluxed for 72 hours. Then, it is cooled to 0 C, and
the crystalline product is suctioned off.
'H-NMR (CDC13) : 6 = 2.40 ppm s (3H) ; 3.73 s (3H) ; 6.33 dd
(J = 10, 2 Hz, 1H); 6.58 d (J = 2 Hz, 1H); 7.03-7.15 m (3H); 7.31
t (J = 10 Hz, 1H); 8.19 d (J = 10 Hz, 1H); 9.72 s (broad)(1H).
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c) 6-Methoxy-l-(3-methylphenyl)-2-phenyl-1H-benzimidazole
was obtained by reaction of 5-methoxy-2-nitrophenyl-m-tolylamine
according to general operating instructions 1 and subsequent
cyclization with triethyl orthobenzoate according to general
operating instructions 3.
1H-NMR (CDC13): 6 = 2.42 ppm s (3H); 3.81 s (3H); 6.69 d (J
2 Hz, 1H); 7.03 dd (J = 8, 2 Hz, 1H); 7.10-7.18 m (2H); 7.30-
7.48 m (5H); 7.62 dd (J = 8, 1 Hz, 2H); 7.89 d (J = 8 Hz, 1H).
d) 6-Hydroxy-l-(3-methylphenyl)-2-phenyl-1H-benzimidazole
was obtained by reaction of 6-methoxy-l-(3-methylphenyl)-2-
phenyl-1H-benzimidazole according to general operating
instructions 6.
1H-NMR (D6-DMSO): 6 = 2.34 ppm s (3H); 6.52 d (J = 2 Hz,
1H); 6.80 dd (J = 8, 2 Hz, 1H); 7.15 d (J = 8 Hz, 1H); 7.28 s
(broad)(1H); 7.32-7.55 m (7H); 7.59 d (J = 8 Hz, 1H); 9.37 s
(broad) (1H) .
6-[[1-(3-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-hydroxy-1-(3-methylphenyl)-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.44-1.58 ppm m (2H) ; 1.64-1.85 m (4H) ;
2.35 t (J = 7.5 Hz, 2H); 2.40 s (3H); 3.68 s (3H); 3.95 t (J =
7.5 Hz, 2H); 6.70 d (J = 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H);
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7.10 d (J = 8 Hz, 1H) 7.16 s (broad) (2H) ; 7.25-7.43 m (4H) ; 7.55
dd (J = 8, 1 Hz, 2H) ; 7.77 d (J = 8 Hz, 1H).
Example 45
6-[[1-(3-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-l-(3-methylphenyl)-2-
phenyl-lH-benzimidazole with 6-bromohexanoic acid isopropylester
according to general operating instructions 8.
1H-NMR (CDC13).: 6 = 1.22 ppm d (J = 8 Hz, 6H).; 1.44-1.56 m
(2H, CH2); 1.64-1.84 m (4H, CH2); 2.30 t (J = 7.5 Hz, 2H); 2.41 s
(3H); 3.95 t (J = 7.5 Hz, 2H); 5.00 sp (J = 8 Hz, 1H); 6.68 d (J
= 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H); 7.10 d (J = 8 Hz, 1H);
7.14 s (broad)(1H); 7.25-7.41 m (4H); 7.54 dd (J = 8, 1 Hz, 2H);
7.75 d (J = 8 Hz, 1H).
Example 46
6-[[1-(3-Methylphenyl)-2-phenyl-1R-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[1-(3-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
1H-NMR (D6-DMSO) : 6 = 1.38-1.80 ppm m (6H); 2.23 t (J = 7.5
Hz, 2H); 3.84-3.93 m (2H); 6.60 d (J = 2 Hz, 1H); 6.87 d (broad)
(J = 8 Hz, 1H); 7.15 d (J = 8 Hz, 2H); 7.20-7.32 m (4H); 7.42-
7.50 m (2H); 7.59 d (J = 8 Hz, 1H); 7.77 d (J = 8 Hz, 1H).
79
Example 47
6-[[1-(3-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexan-l-
of
was obtained by reaction of 6-[[1-(3-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
1H-NMR (CDC13) : 6 = 1.40-1.85 m (8H) ; 2.40 s (3H) ; 3.68 t
(J = 7.5 Hz, 2H); 3.96 t (J = 7.5 Hz, 2H); 6.69 d (J = 1.5 Hz,
1H); 6.96 dd (J = 8, 1.5 Hz, 1H); 7.10 d (J = 8 Hz, 1H); 7.13 s
(broad)(1H); 7.25-7.42 m (5H); 7.54 dd (J = 8, 1 Hz, 2H); 7.76 d
(J = 8 Hz, 1H).
Example 48
6-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 5-Chloro-2-nitrophenyl-p-tolylamine
was produced analogously to 5-chloro-2-nitrophenyl-m-tolylamine
from 1-chloro-3,4-dinitrobenzene and p-toluidine. It was
purified by crystallization.
'H-NMR (CDC13): 6 = 2.40 ppm s (3H); 6.70 dd (J = 10, 2 Hz,
1H), 7.08 d (J = 2 Hz, 1H); 7.16 d (J = 10 Hz, 2H); 7.28 d (J =
Hz, 2H); 8.18 d (J = 10 Hz, 1H); 9.50 s (broad)(1H).
b) 5-Methoxy-2-nitrophenyl-p-tolylamine
was produced analogously to 5-methoxy-2-nitrophenyl-m-tolylamine
from 5-chloro-2-nitrophenyl)-p-tolylamine and sodium methanolate.
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'H-NMR (CDC13): 6 = 2.39 ppm s (3H); 3.72 s (3H); 6.31 dd
(J = 10, 2 Hz, 1H); 6.50 d (J = 2 Hz, 1H); 7.19 d (J = 10 Hz,
2H); 7.25 d (J = 10 Hz, 2H); 8.19 d (J = 10 Hz, 1H); 9.70 s
(broad) (1H) .
c) 6-Methoxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazole
was obtained by reaction of 5-methoxy-2-nitrophenyl-p-tolylamine
according to general operating instructions 1 and subsequent
cyclization with triethyl orthobenzoate according to general
operating instructions 3.
1H-NMR (CDC13) : 6 = 2.49 ppm s (3H) ; 3.80 s (3H) ; 6.69 d (J
2 Hz, 1H); 6.97 dd (J = 8, 2 Hz, 1H); 7.20 d (broad)(J= 8 Hz,
2H); 7.25-7.36 m (5H); 7.53 dd (J = 8, 1 Hz, 2H); 7.76 d (J = 8
Hz, 1H).
d) 6-Hydroxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazole
was obtained by reaction of 6-methoxy-l-(4-methylphenyl)-2-
phenyl-1H-benzimidazole according to general operating
instructions 6.
1H-NMR (D6-DMSO) 6 = 2.40 ppm s (3H); 6.50 d (J = 2 Hz,
1H); 6.80 dd (J = 8, 2 Hz, 1H); 7.28 d (J = 8 Hz, 2H); 7.32-7.43
m (5H); 7.46-7.52 m (2H); 7.56 d (J = 8 Hz, 1H); 9.28 s
(broad) (1H) .
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81
6-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-hydroxy-l-(4-methylphenyl)-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.44-1.58 ppm m (2H) ; 1.62-1.86 m (4H)
2.34 t (J = 7.5 Hz, 2H); 2.48 s (3H); 3.68 s (3H); 3.94 t (J =
7.5 Hz, 2H); 6.69 d (J = 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H);
7.19 d (J = 8 Hz, 2H); 7.28-7.38 m (5H); 7.55 dd (J = 8, 1 Hz,
2H); 7.75 d (J = 8 Hz, 1H).
Example 49
6-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-1-(4-methylphenyl)-2-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
1H-NMR (CDC13): 6 = 1.22 ppm d (J = 7.5 Hz, 6H); 1.44-1.56
m (2H); 1.62-1.85 m (4H); 2.30 t (J = 7.5 Hz, 2H); 2.47 s (3H);
3.93 t (J = 7.5 Hz, 2H); 5.01 sp (J = 7.5 Hz, 1H); 6.68 d (J = 2
Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H); 7.20 d (J = 8 Hz, 2H); 7.26-
7.36 m (5H); 7.55 dd (J = 8, 1 Hz, 2H); 7.75 d (J = 8 Hz, 1H).
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82
Example 50
6-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[1-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 186-190 C
Example 51
6-[[1-(4-Methyiphenyl)-2-phenyl-iH-benzimidazol-6-yl]oxy]hexan-l-
ol
was obtained by reaction of 6-[[1-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
1H-NMR (CDC13): 6 = 1.38-1.80 m (8H); 2.47 s (3H); 3.65 t
(J = 7.5 Hz, 2H); 3.93 t (J = 7.5 Hz, 2H); 6.68 d (J = 2 Hz, 1H);
6.97 dd (J = 8, 2 Hz, 1H); 7.18 d (J = 8 Hz, 2H); 7.24-7.37 m
(5H); 7.54 dd (J = 8, 1 Hz, 2H); 7.75 d (J = 8 Hz, 1H).
Example 52
6-[[1-(3,4-Dimethylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(3,4-Dimethylphenyl)amino-4-nitrophenol
3 g of 3-fluoro-4-nitrophenol and 6.9 g of 3,4-
dimethylaniline were mixed and stirred for 2 hours at 150 C.
After cooling, it was dissolved in dichloromethane and extracted
six times with 1N aqueous hydrochloric acid. The organic phase
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83
was discarded, and the combined aqueous phases were extracted
three times with chloroform. The combined extracts were dried on
sodium sulfate, concentrated by evaporation in a vacuum, and the
residue was chromatographed on silica gel.
'H-NMR (CDC13/D6-DMSO) : 6 = 2.18 ppm s (6H) ; 6.13 dd (J = 8,
2 Hz, 1H); 6.36 d (J = 2 Hz, 1H); 6.90-7.00 m (2H); 7.09 d (J = 8
Hz, 1H); 7.93 d (J = 8 Hz, 1H); 9.50 s (broad)(1H); 10.19 s
(broad) (1H) .
b) 6-[3-(3,4-Dimethyiphenyl)amino-4-nitrophenyl]oxyhexanoic acid
methyl ester
was obtained by reaction of 3-(3,4-dimethylphenyl)amino-4-
nitrophenol with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.38-1.52 ppm m (2H) ; 1.59-1.80 m (4H) ;
2.30 s (6H); 2.33 t (J = 7.5 Hz, 2H); 3.68 s (3H); 3.87 t (J =
7.5 Hz, 2H); 6.28 d (J = 8, 2 Hz, 1H); 6.48 d (J = 2 Hz, 1H);
7.04 d (J = 8 Hz, 1H); 7.06 s (broad)(1H); 7.18 d (J = 8 Hz, 1H);
8.17 d (J = 8 Hz, 1H) : 9.71 s (broad) (, 1H).
6-[[1-(3,4-Dimethylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[3-(3,4-dimethylphenyl) amino-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
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84
'H-NMR (CDC13) : 6 = 1.44-1.56 ppm m (2H) ; 1.62-1.84 m (4H) ;
2.30 s (3H); 2.33 t (J = 7.5 Hz, 2H); 2.34 s (3H); 3.68 s (3H);
3.93 t (J = 7.5 Hz, 2H); 6.67 d (J = 2 Hz, 1H); 6.94 dd (J = 8, 2
Hz, 1H); 7.03 dd (J = 8, 1.5 Hz, 1H); 7.09 s (broad)(1H); 7.22-
7.35 m (4H); 7.57 dd (J = 8, 1.5 Hz, 2H); 7.76 d (J = 8 Hz, 1H).
Example 53
6-[[1-(3,4-Dimethylphenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[1-(3,4-dimethylphenyl)-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 158-161 C
Example 54
6--[[1-(3,5-Dimethylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(3,5-Dimethylphenyl)amino-4-nitrophenol
5.4 g of 3-fluoro-4-nitrophenol and 4.3 ml of 3,5-
dimethylaniline were mixed and stirred for 6 hours at 120 C.
After cooling, it was taken up in ethyl acetate and water and
extracted three times with 1N aqueous hydrochloric acid. The
combined aqueous phases were extracted three times with ethyl
acetate. The combined organic phases were dried on sodium
sulfate, concentrated by evaporation in a vacuum, and the residue
was crystallized.
CA 02396227 2002-07-04
'H-NMR (D6-DMSO): 6 = 2.30 ppm s (6H); 6.28 dd (J = 8, 2
Hz, 1H); 6.49 d (J = 2 Hz, 1H); 6.52 d (J = 2 Hz, 1H); 6.90 s
(broad)(1H); 6.98 s (broad)(2H); 8.04 d (J = 8 Hz, 1H); 9.51 s
(broad) (1H) .
b) 6-[3-(3,5-Dimethylphenyl)amino-4-nitrophenyl]oxyhexanoic acid
methyl ester
was obtained by reaction of 3-(3,5-dimethylphenyl)amino-4-
nitrophenol with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
'H-NMR (CDC13) : 6 = 1.40-1.52 ppm m (2H) ; 1.60-1.80 m (4H) ;
2.30 t (J = 7.5 Hz, 2H); 2.32 s (6H); 3.68 s (3H); 3.88 t (J =
7.5 Hz, 2H); 6.30 dd (J = 8, 2 Hz, 1H); 6.52 d (J = 2 Hz, 1H);
6.88 s (broad) (1H) ; 6.91 s (broad) (2H) ; 8.17 d (J = 8 Hz, 1H) ;
9.69 s (broad) (1H) .
6-[3-(3,5-Dimethylphenyl)amino-4-nitrophenyl]oxyhexanoic acid
methyl ester
was obtained by reaction of 6-[3-(3,5-dimethylphenyl)amino-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
Flash point 124-126 C
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86
Example 55
6-[[1-(3,5-Dimethylphenyl)-2-phenyl-lH-benzimidazol-6-
yl] oxy] hexanoic acid
was by reaction of 6-[3-(3,5-dimethylphenyl) amino-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 9.
Flash point 162-164 C
Example 56
6-[[1-(3,5-Dimethylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
was by reaction of 6-[3-(3,5-dimethylphenyl)amino-4-
nitrophenyl]oxyhexanoic acid with isopropanol according to
general operating instructions 10.
Flash point 98-101 C
Example 57
6-[[1-(3-Methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(3-Methoxyphenyl)amino-4-nitrophenol
4 g of 3-fluoro-4-nitrophenol and 9.4 g of m-anisidine were
mixed and stirred for 2.5 hours at 150 C. After cooling, it was
dissolved in dichloromethane and extracted three times with 1N
aqueous hydrochloric acid. The organic phase was dried on sodium
sulfate, concentrated by evaporation in a vacuum, and the residue
was chromatographed on silica gel.
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'H-NMR (CDC13): 6 = 3.83 ppm s (3H); 6.30 dd (J = 10, 2 Hz,
1H); 6.57 d (J = 2 Hz, 1H); 6.70-6.84 m (2H); 6.89 d (broad)(J =
Hz, 1H); 7.32 t (J = 10 Hz, 1H); 8.19 d (J = 10 Hz, 1H); 9.68
s (broad)(1H); 9.69 s (broad).
b) 6-[3-(3-Methoxyphenyl)amino-4-nitrophenyl]oxyhexanoic acid
methyl ester
was obtained by reaction of 3-(3-methoxyphenyl)amino-4-
nitrophenol with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.42-1.58 ppm m (2H) ; 1.60-1.93 m (4H) ;
2.34 t (J = 7.5 Hz, 2H); 3.68 s (3H); 3.80 s (3H); 4.03 t (J =
7.5 Hz, 2H); 6.32 dd (J = 10, 2 Hz, 1H); 6.59 d (J = 2 Hz, 1H);
6.68-6.84 m (2H); 6.90 d (broad)(J = 8 Hz, 1H): 7.32 t (J = 8 Hz,
1H); 8.19 d (J = 10 Hz, 1H); 9.70 s (broad)(1H).
6-[[1-(3-Methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[3-(3-methoxyphenyl)amino-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
1H-NMR (CDC13) : 6 = 1.44-1.58 ppm m (2H) ; 1.62-1.86 m (4H) ;
2.34 t (J = 7.5 Hz, 2H); 3.68 s (3H); 3.78 s (3H); 3.95 t (J =
7.5 Hz, 2H); 6.71 d (J = 1.5 Hz, 1H); 6.83 dd (J = 1.5, 1.5 Hz,
1H) ; 6.90 dd (J = 8, 1.5 Hz, 1H); 6.94 dd (J = 8, 1.5 Hz, 1H);
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7.01 dd (J = 8, 1.5 Hz, 1H); 7.27-7.36 m (3H); 7.40 t (J = 8 Hz,
1H); 7.56 dd (J = 8, 2 Hz, 2H); 7.74 d (J = 8 Hz, 1H).
Example 58
6-[[1-(3-Methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[1-(3-methoxyphenyl)-2-phenyl-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 149-152 C
Example 59
6-[[1-(4-Methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(4-Methoxyphenyl)amino-4-nitrophenol
0.16 g of 3-fluoro-4-nitrophenol and 0.37 g of p-anisidine
were mixed and stirred for 1.5 hours at 150 C. After cooling, it
was dissolved in dichloromethane, and extracted twice with iN
aqueous hydrochloric acid and once with saturated sodium chloride
solution. The organic phase was dried on sodium sulfate and
concentrated by evaporation in a vacuum.
1H-NMR (CDC13/D6-DMSO) : 5 = 3.57 ppm s (3H) ; 6.06 dd (J =
10, 2 Hz, 1H); 6.18 d (J = 2 Hz, 1H); 6.77 d (J = 10 Hz, 2H);
7.03 d (J = 10 Hz, 2H); 7.89 d (J = 10 Hz, 1H); 9.40 s
(broad)(1H); 9.80 s (broad).
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b) 6-[3-(4-Methoxyphenyl)amino-4-nitrophenyl]oxyhexanoic acid
methyl ester
was obtained by reaction of 3-(4-methoxyphenyl)amino-4-
nitrophenol with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.38-1.50 ppm m (2H) ; 1.60-1.80 m (4H) ;
2.33 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.85 t (J = 7.5 Hz, 2H);
3.88 s (3H); 6.29 dd (J = 10, 1.5 Hz, 1H); 6.30 d (J = 1.5 Hz,
1H); 6.98 d (J = 10 Hz, 2H); 7.20 d (J = 10 Hz, 2H); 8.18 d (J =
Hz, 1H); 9.63 s (broad)(1H).
6-[[1-(4-Methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[3-(4-methoxyphenyl)amino-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
Flash point 98-102 C
Example 60
6-[[1-(4-Methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[1-(4-methoxyphenyl)-2-phenyl-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 160-165 C
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Example 61
6-[[1-(3,4-Dimethoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(3,4-Dimethoxyphenyl)amino-4-nitrophenol
3 g of 3-fluoro-4-nitrophenol and 8.8 g of 3,4-
dimethoxyaniline were mixed and stirred for 2 hours at 150 C.
After cooling, it was dissolved in dichloromethane and extracted
twice with 1N aqueous hydrochloric acid. The aqueous phase was
extracted twice with chloroform, and the combined chloroform
extracts were dried on sodium sulfate and concentrated by
evaporation.in a vacuum.
1H-NMR (D6-DMSO) : 6 = 3.75 ppm s (3H) ; 3.78 s (3H) ; 6.25 dd
(J = 10, 2 Hz, 1H); 6.35 d (J = 2 Hz, ]H); 6.88 dd (J = 8, 1.5
Hz, 1H); 6.98 d (J = 1.5 Hz, 1H); 7.05 d (J = 8 Hz, 1H); 8.04 d
(J = 10 Hz, 1H); 9.52 s (broad)(1H); 10.72 s (broad).
b) 6-[3-(3,4-Dimethoxyphenyl)amino-4-nitrophenyl]oxyhexanoic
acid methyl ester
was obtained by reaction of 3-(3,4-dimethoxyphenyl)amino-4-
nitrophenol with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
1H-NMR (CDC13) : 6 = 1.40-1.52 ppm m (2H) ;- 1.60-1.80 m (4H) ;
2.32 t (J = 7.5 Hz, 2H); 3.68 s (3H); 3.85 t (J = 7.5 Hz, 2H);
3.88 s (3H); 3.93 s (3H); 6.29 dd (J = 10, 1.5 Hz, 1H); 6.33 d (J
= 1.5 Hz, 1H); 6.80 d (J = 1.5 Hz, 1H); 6.87 dd (J = 10, 1.5 Hz,
1H); 6.92 d (J = 10 Hz, 1H); 8.18 d (J = 10 Hz, 1H); 9.68 s
(broad) (1H) .
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6-[[1-(3,4-Dimethoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[3-(3,4-dimethoxyphenyl)amino-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
Flash point 116-118 C
Example 62
6-[[1-(3,4-Dimethoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[1-(3,4-dimethoxyphenyl)-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 158-161 C
Example 63
6-[[1-[3,4-(Methylenedioxy)phenyl]-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(3,4-Methylenedioxyphenyl)amino-4-nitrophenol
0.86 g of 3-fluoro-4-nitrophenol and 2.25 g of 3,4-
methylenedioxyaniline were mixed and stirred for 5 hours at
120 C. The raw mixture was chromatographed on silica gel.
'H-NMR (D6-DMSO) : 6 = 6.02 ppm s (2H) ; 6.25 dd (J = 10, 2
Hz, 1H); 6.33 d (J = 2 Hz, 1H); 6.72 dd (J = 8, 1.5 Hz, 1H); 6.87
d (J = 1.5 Hz, 1H); 7.05 d (J = 10 Hz, 1H); 8.18 d (J = 10 Hz,
1H) ; 9.52 s (broad) (1H) .
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b) 6-[3-(3,4-Methylenedioxyphenyl)amino-4-nitrophenyl]oxy-
hexanoic acid methyl ester
was obtained by reaction of 3-(3,4-methylenedioxyphenyl)amino-4-
nitrophenol with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
Flash point 108-111 C
6-[[1-(3,4-Methylenedioxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[3-(3,4-methylenedioxyphenyl)amino-
4-nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
1H-NMR (CDC13) :_ 6 = 1.43-1.55 ppm m (2H); 1.65-1.82 m (4H) ;
2.35 t (J = 7.5 Hz,=2H); 3.68 s (3H); 3.95 t (J = 7.5 Hz, 2H);
6.10 s (2H); 6.65 d (J = 1.5 Hz, 1H); 6.72-6.83 m (2H); 6.90 d (J
= 10 Hz, 1H); 6.93 dd (J = 10, 1.5 Hz, 1H); 7.29-7.38 m (3H);
7.52-7.62 m (2H); 7.72 d (J = 10 Hz, 1H).
Example 64
6-[[1-[3,4-(Methylenedioxy)phenyl]-2-phenyl-lH-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[1-(3,4-methylenedioxyphenyl)-2-
phenyl-lH-benzimidazol-6-yl]oxy]hexanoic acid methyl ester
according to general operating instructions 9.
Flash point 130 C
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Example 65
6-[[2-Phenyl-l-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 3-(3,4,5-Trimethoxyphenyl)amino-4-nitrophenol
3.7 g of 3-fluoro-4-nitrophenol and 4.76 g of 3,4,5-
trimethoxyaniline were mixed and stirred for 10 hours at 100 C.
After cooling, it was taken up in ethyl acetate and water and
extracted three times with ethyl acetate. The combined organic
phases were extracted three times with iN aqueous hydrochloric
acid and once with saturated sodium chloride solution, dried on
sodium sulfate and concentrated by evaporation to a very large
extent in a vacuum. The product was digested with diisopropyl
ether.
1H-NMR (D6-DMSO) : 6 = 3.70 ppm s (3H) ; 3.80 s (6H) ; 6.28 dd
(J = 10, 2 Hz, 1H); 6.53 d (J = 2 Hz, 1H); 6.70 s (2H); 8.05 d (J
Hz, 1H); 9.50 s (broad)(1H); 10.71 s (broad).
b) 6-[4-Nitro-3-[(3,4,5-trimethoxyphenyl)amino]-
phenyl]oxyhexanoic acid methyl ester
was obtained by reaction of 4-nitro-3-[(3,4,5-
trimethoxyphenyl)amino]phenol with 6-bromohexanoic acid methyl
ester according to general operating instructions 8.
1H-NMR (CDC13): 6 = 1.40-1.53 ppm m (2H); 1.60-182 m (4H);
2.32 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.85 s (6H); 3.88 t (J =
7.5 Hz, 2H); 3.90 s (3H); 6.30 dd (J = 10, 1.5 Hz, 1H); 6.50 d (J
= 1.5 Hz, 1H); 6.52 s (2H); 8.18 d (J = 10 Hz, 1H); 9.68 s
(broad) (1H) .
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6-[[2-Phenyl-l-(3,4,5=trimethoxyphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[4-nitro-3-[(3,4,5-
trimethoxyphenyl) amino] phenyl] oxy-hexanoic acid methyl ester
according to general operating instructions 1 and subsequent
cyclization with triethyl orthobenzoate according to general
operating instructions 3.
Flash point 128-130 C
Example 66
6-[[2-Phenyl-l-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[2-phenyl-l-(3,4,5-
trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl
ester according to general operating instructions 9.
Flash point 198-201 C
Example 67
6-[[2-Phenyl-l-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
was obtained by reaction of 6-[[2-phenyl-l-(3,4,5-
trimethoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid with
isopropanol according to general operating instructions 10.
Flash point 98-101 C
95
Example 68
6-[[1-(4-(N,N-Dimethylamino)phenyl]-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) N,N-Dimethyl-N'-(5-chloro-2-nitrophenyl)benzene-1,4-diamine
was produced analogously to 5-chloro-2-nitrophenyl-m-tolylamine
from 1-chloro-3,4-dinitrobenzene and N,N-dimethyl-p-
phenylenediamine.
IH-NMR (CDC13) 6 = 3.01 ppm s (6H); 6.63 dd (J = 10, 2 Hz,
1H); 6.80 d (broad)(J = 10 Hz, 2H); 6.97 d (J = 2 Hz, 1H); 7.14 d
(J = 10 Hz, 2H); 8.14 d (J = 10 Hz, 1H); 9.42 s (broad)(1H).
b) N,N-Dimethyl-N'-(5-methoxy-2-nitrophenyl)benzene-1,4-diamine
24.9 g of N,N-dimethyl-N'-(5-chloro-2-nitrophenyl)benzene-
1,4-diamine was added to a solution that consists of 8 g of
sodium in 200 ml of methanol, and the mixture was heated in an
autoclave for 9 hours to 120 C. After cooling, crystalline
product was suctioned out.
1H-NMR (CDC13): 6 = 3.00 ppm s (6H); 3.70 s (3H); 6.25 dd
(J = 10, 2 Hz, 1H); 6.34 d (J = 2 Hz, 1H); 6.78 d (J = 10 Hz,
2H); 7.14 d (J = 10 Hz, 2H); 8.16 d (J = 10 Hz, 1H); 9.67 s
(broad) (1H) .
c) 6-Methoxy-l-[4-(N,N-dimethylamino)phenyl]-2-phenyl-lH-
benzimidazole
was produced by reaction of ,N,N-dimethyl-N'-(5-methoxy-2-
nitrophenyl) benzene- 1,4-diamine according to general operating
instructions 1, subsequent reaction of the crude diamine with
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trimethyl orthobenzoate according to general operating
instructions 3 and subsequent refluxing of the crude product with
6N aqueous hydrochloric acid for 1 hour. After the reaction
mixture was alkalized with aqueous sodium hydroxide solution, it
was extracted with ethyl acetate, dried on sodium sulfate and
concentrated by evaporation in a vacuum.
1H-NMR (CDC13) : 6 = 3.04 ppm s (6H); 3.80 s (3H); 6.68 d (J
2 Hz, 1H); 6.78 d (J = 10 Hz, 2H); 6.95 dd (J = 10, 2 Hz, 1H);
7.17 d (J = 10 Hz, 2H); 7.25-7.33 m (3H); 7.56-7.64 m (2H); 7.74
d (J = 10 Hz, 1H).
d) 6-Hydroxy-l-[4-(N,N-dimethylamino)phenyl]-2-phenyl-lH-
benzimidazole
was obtained by reaction of 6-methoxy-l-[4-(N,N-
dimethylamino)phenyl]-2-phenyl-1H-benzimidazole according to
general operating instructions 6.
1H-NMR (D6-DMSO): 6 = 2.98 ppm s (6H); 6.48 d (J = 2 Hz,
1H); 6.78 dd (J = 10, 2 Hz, 1H); 6.83 d (J = 10 Hz, 2H); 7.17 d
(J = 10 Hz, 2H); 7.30-7.38 m (3H); 7.50-7.57 m (3H); 9.32 s
(broad) (1H) .
6-[(1-[4-(N,N-Dimethylamino)phenyl]-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-hydroxy-l-[4-(N,N-
dimethylamino)phenyl]-2-phenyl-1H-benzimidazole with 6-
bromohexanoic acid methyl ester according to general operating
instructions 8.
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'H-NMR (CDC13) : 6 = 1.43-1.57 ppm m (2H) ; 1.64-1.85 m (4H) ;
2.33 t (J = 7.5 Hz, 2H); 3.05 S (6H); 3.67 s (3H); 3.93 t (J =
7.5 Hz, 2H); 6.65 d (J = 2 Hz, 1H); 6.76 d (J = 10 Hz, 2H); 6.93
dd (J = 10, 2 Hz, 1H); 7.14 d (J = 10 Hz, 2H); 7.23-7.27 m (3H);
7.62 dd (J = 10, 1.5 Hz, 2H); 7.74 d (J = 10 Hz, 1H).
Example 69
6-[[1-[4-(N,N-Dimethylamino)phenyl]-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[1-[4-(N,N-dimethylamino)phenyl]-
2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester
according to general operating instructions 9.
Flash point 210-213 C
Example 70
6-[[1-(4-Biphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy] hexanoic
acid methyl ester
a) 5-Chloro-2-nitrophenyl-4-biphenylamine
was produced analogously to 5-chloro-2-nitrophenyl-m-tolylamine
from 1-chloro-3,4-dinitrobenzene and 4-biphenylamine. It was
purified by chromatography on silica gel.
'H-NMR (CDC13): 6 = 6.76 dd (J = 10, 2 Hz, 1H); 7.26 d (J =
2 Hz, 1H); 7.35 d (J = 8 Hz, 1H); 7.32-7.52 m (4H); 7.60-7.72 m
(4H); 8.19 d (J = 10 Hz, 1H); 9.60 s (broad)(1H).
98
b) 5-Methoxy-2-nitrophenyl-4-biphenylamine
was produced analogously to 5-methoxy-2-nitrophenyl-m-tolylamine
from 5-chloro-2-nitrophenyl-4-biphenylamine and sodium
methanolate.
Flash point 150-154 C
b) 1-(4-Biphenyl)-6-methoxy-2-phenyl-lH-benzimidazole
was obtained by reaction of 5-methoxy-2-nitrophenyl-4-
biphenylamine according to general operating instructions 1 and
subsequent cyclization with triethyl orthobenzoate according to
general operating instructions 3.
Flash point 140-144 C
c) 1-(4-Biphenyl)-6-hydroxy-2-phenyl-lH-benzimidazole
was obtained by reaction of 1-(4-biphenyl)-6-methoxy-2-phenyl-lH-
benzimidazole according to general operating instructions 6.
Flash point 312 C
6-[[1-(4-Biphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 1-(4-biphenyl)-6-hydroxy-2-phenyl-lH-
benzimidazole with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
Flash point 106-108 C
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Example 71
6-[[1-(4-Biphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[1-(4-biphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 5.
1H-NMR (D6-DMSO) : 6 = 1.35-1.78 ppm m (6H); 2.20 t (J = 7.5
Hz, 2H); 3.96 m (2H); 6.72 d (J = 2 Hz, 1H); 6.97 dd (J = 10, 2
Hz, 1H); 7.32-7.58 m (10H); 7.69 d (J = 10 Hz, 1H); 7.80 d (J = 8
Hz, 2H); 7.89 d (J = 10 Hz, 2H)'.
Example 72
6-[[1-(2-Naphthyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 3-(2-Naphthylamino)-4-nitrophenol
3 g of 3-fluoro-4-nitrophenol and 8.2 g of 2-naphthylamine
were mixed and stirred for 8 hours at 180 C. The raw mixture was
taken up in chloroform and washed with 2N aqueous hydrochloric
acid. The organic phase was dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
1H-NMR (D6-DMSO) : 6 = 6.02 ppm s (2H) ; 6.25 dd (J = 10, 2
Hz, 1H); 6.33 d (J = 2 Hz, 1H); 6.72 dd (J = 8, 1.5 Hz, 1H); 6.87
d (J = 1.5 Hz, 1H); 7.05 d (J = 10 Hz, 1H); 8.18 d (J = 10 Hz,
1H) ; 9.52 s (broad) (1H) .
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b) 6-(3-(2-Naphthyl)amino-4-nitrophenylloxyhexanoic acid methyl
ester
was obtained by reaction of 3-(2-naphthylamino)-4-nitrophenol
with 6-bromohexanoic acid methyl ester according to general
operating instructions 8.
1H-NMR (CDC13) : 6 = 1.35-1.49 ppm m (2H) ; 1.60-1.80 m (4H)
2.30 t (J = 7.5 Hz, 2H); 3.64 s (3H); 3.84 t (J = 7.5 Hz, 2H);
6.35 dd (J = 10, 2 Hz, 1H); 6.62 d (J = 2 Hz, 1H); 7.43 dd (J =
10, 2 Hz, 1H); 7.48-7.57 m (2H); 7.75 d (J = 2 Hz, 1H); 7.78-7.90
m (2H); 7.91 d (J = 10 Hz, 1H); 8.21 d (J = 10 Hz, 1H); 9.92 s
(broad) (1H) .
6-[[1-(2-Naphthyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-[3-(2-naphthylamino)-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
Flash point 111-114 C
Example 73
6-[[1-(2-Naphthyl)-2-phenyl-lH-benzimidazol-6-ylloxylhexanoic
acid
was obtained by reaction of 6-[[1-(2-naphthyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 170-175 C
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101
Example 74
6-[[1-(2-Fluorenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 3-(2-Fluorenylamino)-4-nitrophenol
2.17 g of 3-fluoro-4-nitrophenol and 5 g of 2-aminofluorene
were mixed and stirred for 9 hours at 140 C. The raw mixture was
taken up in ethyl acetate and water and washed with 1N aqueous
hydrochloric acid. The aqueous phase was extracted with ethyl
acetate, and the combined organic phases were washed three times
with 2N aqueous hydrochloric acid and once with saturated sodium
chloride solution, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue was chromatographed on
silica gel.
1H-NMR (D6-DMSO) : 6 = 3.96 ppm s (2H) ; 6.30 dd (J = 10, 2
Hz, 1H); 6.52 d (J = 2 Hz, 1H); 7.28-7.45 in (3H); 7.57 s
(broad)(1H); 7.60 d (J = 8 Hz, 1H); 7.92 d (J = 8 Hz, 1H); 7.98 d
(J = 8 Hz, 1H); 8.10 d (J = 10 Hz, 1H); 9.70.s (1H); 10.80 s
(broad) (1H) .
b) 6-[3-(2-Fluorenylamino)-4-nitrophenyl]oxyhexanoic acid methyl
ester
was obtained by reaction of 3-(2-fluorenylamino)-4-nitrophenol
with 6-bromohexanoic acid methyl ester according to general
operating instructions 8.
1H-NMR (CDC13) : 6 = 1.38-1.50 ppm m (2H) ; 1.58-1.80 m (4H) ;
2.30 t (J = 7.5 Hz, 2H); 3.65 s (3H); 3.84 t (J = 7.5 Hz, 2H);
3.95 s (2H); 6.31 dd (J = 10, 2 Hz, 1H); 6.53 d (J = 2 Hz, 1H);
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7.33 t (J = 8 Hz, 2H); 7.42 t (J = 8 Hz, 1H); 7.47 s (1H); 7.58 d
(J = 8 Hz, 1H); 7.80 d (J = 8 Hz, 1H), 7.83 d (J = 8 Hz, 1H);
8.21 d (J = 10 Hz, 1H); 9.87 s (broad)(1H).
6-[[1-(2-Fluorenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-[3-(2-fluorenyl)amino)-4-
nitrophenyl]oxyhexanoic acid methyl ester according to general
operating instructions 1 and subsequent cyclization with triethyl
orthobenzoate according to general operating instructions 3.
Flash point 125-128 C
Example 75
6-[[1-Phenyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) Ethyl-(3-trifluoromethyl)benzimidate hydrochloride
9.7 ml of 3-(trifluoromethyl)benzonitrile was dissolved in
12 ml of ethanol, and the solution was saturated with HC1 gas
while being.Cooled in an ice bath. After 72 hours, precipitated
product was suctioned out. The product was washed with diethyl
ether.
Flash point 131-133 C (decomposition)
b) 5-Methoxy-2-nitrophenyldiphenylamine
A solution that consists of 2 g of 3-fluoro-4-nitroanisole
in 16 ml of aniline was stirred for 24 hours at 140 C. After
cooling, it was taken up in ethyl acetate and extracted with 2N
CA 02396227 2002-07-04
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aqueous hydrochloric acid. The organic phase was dried on sodium
sulfate and concentrated by evaporation in a vacuum. The residue
was chromatographed on silica gel.
'H-NMR (CDC13) 6 = 3.72 ppm s (3H) ; 6.36 dd (J = 10, 2 Hz,
1H); 6.57 d (J = 2 Hz, 1H); 7.22-7.33 m (3H); 7.44 dd (J = 8, 8
Hz, 2H); 8.18 d (J = 10 Hz, 1H); 9.78 s (broad)(1H).
c) 4-Methoxy-N2-phenyl-o-phenylenediamine
was obtained by reaction of 5-methoxy-2-nitrophenyldiphenylamine
according to general operating instructions 1.
'H-NMR (CDC13) : 6 = 3.42 ppm s (broad) (2H) ; 3.72 s (3H) ;
5.33 s (broad)(1H); 6.56 dd (J = 10, 2 Hz, 1H); 6.76 d (J = 10
Hz, 1H); 6.79 d (J = 2 Hz, 1H); 6.82-6.90 m (3H); 7.25 dd (J =
8.8 Hz, 2H)
d) 6-Methoxy-l-phenyl-2-[3-(trifluoromethyl)phenyl]-1H-
benzimidazole
was obtained by reaction of 4-methoxy-N2-phenyl-o-
phenylenediamine with ethyl-(3-trifluoromethyl)benzimidate
hydrochloride according to general operating instructions 4.
Flash point 138-140 C
e) 6-Hydroxy-1-phenyl-2-[3-(trifluoromethyl)phenyl]-1H-
benzimidazole
was obtained by reaction of 6-methoxy-l-phenyl-2-[3-
(trifluoromethyl)phenyl]-1H-benzimidazole according to general
operating instructions 7.
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1H-NMR (D6-DMSO): 6 = 6.60 ppm d (J = 2 Hz, 1H) ; 6.99 dd (J
10, 2 Hz, 1H); 7.50-7.89 m (10H).
6-[[l-Phenyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-hydroxy-l-phenyl-2-[3-
(trifluoromethyl)phenyl]-1H-benzimidazole with 6-bromohexanoic
acid methyl ester according to general operating instructions 8.
Flash point 68-70 C
Example 76
6-[[1-Phenyl-2-(3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
was obtained by reaction of 6-hydroxy-l-phenyl-2-[3-
(trifluoromethyl)phenyl]-1H-benzimidazole with 6-bromohexanoic
acid isopropyl ester according to general operating instructions
8.
Flash point 96-98 C
Example 77
6-[[l-Phenyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was obtained by reaction of 6-[[l-phenyl-2-[3-
(trifluoromethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester according to general operating instructions 9.
1H-NMR (D6-DMSO) : 6 = 1.38-1.80 ppm m (6H) ; 2.27 t (J = 7.5
Hz, 2H); 3.98 t (J = 7.5 Hz, 2H); 6.70 d (J = 2 Hz, 1H); 7.02 dd
105
(J = 10, 2 Hz, 1H); 7.48-7.88 m (9H); 7.77 d (J = 10 Hz, 1H);
11.94 s (broad) (1H) .
Example 78
6-[[1-Phenyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-6-
yl] oxy] hexan-l-ol
was obtained by reaction of 6-[[1-phenyl-2-[3-
(trifluoromethyl)phenyl]-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester according to general operating instructions 11.
1H-NMR (CDC13): 6 = 1.38-1.68 ppm m (6H); 1.75-1.87 m (2H);
3.60-3.72 m (2H); 3.94 t (J = 7.5 Hz, 2H); 6.69 d (J = 2 Hz, 1H);
6.99 dd (J = 10, 2 Hz,. 1H); 7.25-7.35 m (2H); 7.40 dd (J = 8.8
Hz; 1H); 7.50-7.61 m (4H); 7.68 d (broad)(J = 8 Hz, 1H); 7.78 d
(J = 10 Hz, 1H) ; 7.83 s (broad) (1H) .
Example 79 -
6-[[2-(3-Chlorophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 2-(3-Chlorophenyl)-6-methoxy-l-phenyl-lH-benzimidazole
was obtained by reaction of 4-methoxy-N2-phenyl-o-
phenylenediamine with ethyl-3-chlorobenzimidate hydrochloride
(produced according to: DeWolfe and Augustine; J. Org. Chem.;
30; 699) according to general operating instructions 4.
Flash point 149-151 C
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106
b) 2-(3-Chlorophenyl)-6-hydroxy-l-phenyl-1H-benzimidazole
was obtained by reaction of 2-(3-chlorophenyl)-6-methoxy-l-
phenyl-lH-benzimidazole according to general operating
instructions 7.
Flash point 199-202 C
6-[[2-(3-Chlorophenyl)-1-phenyl-iH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 2-(3-chlorophenyl)-6-hydroxy-l-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 69-72 C
Example 80
6-[[2-(3-Chlorophenyl)-1-phenyl-lH-benzimidazol-6-yl-]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 2-(3-chlorophenyl)-6-hydroxy-l-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 98-100 C
Example 81
6-[[2-(3-Chlorophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[2-(3-chlorophenyl)-i-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
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Flash point 137-140 C
Example 82
6-[[2-(3-Chlorophenyl)-l-phenyl-iH-benzimidazol-6-yl]oxy]hexan-l-
ol
was obtained by reaction of 6-[[2-(3-chlorophenyl)-1-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
1H-NMR (CDC13) : 6 = 1.40-1.70 ppm m (6H) ; 1.75-1.86 m (2H);
3.67 t (J = 7.5 Hz, 2H); 3.93 t (J = 7.5 Hz, 2H); 6.69.d (J = 2
Hz, 1H); 6.99 dd (J = 10, 2 Hz, 1H); 7.20 dd (J = 8.8 Hz; 1H);
7.26-7.38 m (4H); 7.47-7.58 m (3H); 7.60 dd (J = 2.2 Hz, 1H);
7.76 d (J = 10 Hz, 1H).
Example 83
6-[[2-(4-Chlorophenyl)-l-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) Ethyl-4-chlorobenzimidate hydrochloride
g of 4-chlorobenzonitrile was suspended in 12 ml of
ethanol and dissolved by adding diethyl ether. While being
cooled in an ice bath, it was saturated with HC1 gas. After 72
hours, precipitated product was suctioned out. The product was
washed with diethyl ether.
Flash point 173-174 C (decomposition)
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108
a) 2-(4-Chiorophenyl)-6-methoxy-l-phenyl-1H-benzimidazole
was obtained by reaction of 4-methoxy-N2-phenyl-o-
phenylenediamine with ethyl-4-chlorobenzimidate hydrochloride
according to general operating instructions 4.
Flash point 162-164 C
b) 2-(4-Chiorophenyl)-6-hydroxy-l-phenyl-lH-benzimidazole
was obtained by reaction of 2-(4-chlorophenyl)-6-methoxy-l-
phenyl-1H-benzimidazole according to general operating
instructions 7.
Flash point 246-250 C
6-[[2-(4-Chiorophenyl)-l-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 2-(4-chlorophenyl)-6-hydroxy-l-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 86-87 C
Example 84
6-[[2-(4-Chiorophenyl)-l-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 2-(4-chlorophenyl)-6-hydroxy-l-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 124-126 C
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109
Example 85
6-[[2-(4-Chlorophenyl)-l-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[2-(4-chlorophenyl)-1-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
'H-NMR (D6-DMSO) : 6 = 1.35-1.48 ppm m (2H) ; 1.50-1.62 m
(2H); 1.64-1.77 m (2H); 2.23 t (J = 7.5 Hz, 2H); 3.91 t (J = 7.5
Hz, 2H); 6.64 d (J = 2 Hz, 1H); 6.96 dd (J = 10, 2 Hz, 1H); 7.38-
7.50 m (6H); 7.52-7.65 m (3H); 7.70 d (J = 10 Hz, 1H).
Example 86
6-[[2-(4-Chlorophenyl)-l-phenyl-lH-benzimidazol-6-yl]oxy]hexan-l-
of
was obtained by reaction of 6-[[2-(4-chlorophenyl)-1-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
1H-NMR (CDC13) 6 = 1.38-1.68 ppm m (6H); 1.74-1.85 m (2H)
3.67 t (broad)(J = 7.5 Hz, 2H); 3.94 t (J = 7.5 Hz, 2H); 6.68 d
(J = 2 Hz, 1H); 6.98 dd (J = 10, 2 Hz, 1H); 7.22-7.35 m (5H);
7.47 d (J = 8 Hz; 2H); 7.49-7.59 m (2H); 7.73 d (J = 10 Hz, 1H).
110
Example 87
6-[[2-(3-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 6-Methoxy-2-(3-methylphenyl)-1-phenyl-lH-benzimidazole
was obtained by reaction of 4-methoxy-N2-phenyl-o-
phenylenediamine with ethyl-3-methylbenzimidate hydrochloride
(produced according to: DeWolfe and Augustine; J. Org. Chem.;
30; 699) according to general operating instructions 4.
Flash point 156-158 C
b) 6-Hydroxy-2-(3-methylphenyl)-l-phenyl-1H-benzimidazole
was obtained by reaction of 6-methoxy-2-(3-methylphenyl)-i-
phenyl-1H-benzimidazole according to general operating
instructions 7.
1H-NMR (D6-DMSO) : 6 = 2.23 ppm s (M); 6.52 d (J = 2 Hz,
1H); 6.80 dd (J = 10, 2 Hz, 1H); 7.18 s (broad)(3H); 7.35-7.52 m
(3H) ; 7.50-7.63 m (4H) ; 9.28 s (broad) (1H) .
6-[[2-(3-Methyiphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-hydroxy-2-(3-methylphenyl)-1-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 82-84 C
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111
Example 88
6-[[2-(3-Methylphenyl)-l-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-2-(3-methylphenyl)-1-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
1H-NMR (CDC13): 6 = 1.22 ppm d (J = 7.5 Hz, 6H); 1.38-1.56
m (2H); 1.62-1.85 m (4H); 2.30 t (J = 7.5 Hz, 2H); 2.30 s (3H);
3.93 t (J = 7.5 Hz, 2H); 5.00 sp (J = 7.5 Hz, 1H); 6.68 d (J = 2
Hz, 1H); 6.95 dd (J = 10, 2 Hz, 1H); 7.13 s (broad)(3H); 7.31 dd
(J = 8, 2 Hz, 2H); 7.42-7.57 m (4H); 7.76 d (J = 10 Hz, 1H).
Example 89
6-[[2-(3-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[2-(3-methylphenyl)-1-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
1H-NMR (D6-DMSO) : 6 = 1.35-1.49 ppm m (2H); 1.50-1.63 m
(2H); 1.64-1.78 m (2H); 2.22 t (J = 7.5 Hz, 2H); 2.24 s (3H);
3.92 t (J = 7.5 Hz, 2H); 6.62 d (J = 2 Hz, 1H); 6.95 dd (J = 10,
2 Hz, 1H); 7.18 s (broad)(3H); 7.37-7.42 m (3H); 7.51-7.65 m
(3H) ; 7.67 d (J = 10 Hz, 1H) ; 11.90 s (broad) (1H)
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112
Example 90
6-[[2-(3-Methylphenyl)-1-phenyl-iH-benzimidazol-6-yl]oxy]hexan-l-
of
was obtained by reaction of 6-[[2-(3-methylphenyl)-1-phenyl-iH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 92-94 C
Example 91
6-[[2-(4-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 6-Methoxy-2-(4-methylphenyl)-1-phenyl-lH-benzimidazole
was obtained by reaction of 4-methoxy-N2-phenyl-o-
phenylenediamine with ethyl-4-methylbenzimidate hydrochloride
(produced according to: DeWolfe and Augustine; J. Org. Chem.;
30; 699) according to general operating instructions 4.
Flash point 150-152 C
b) 6-Hydroxy-2-(4-methylphenyl)-1-phenyl-lH-benzimidazole
was obtained by reaction of 6-methoxy-2-(4-methylphenyl)-i-
phenyl-1H-benzimidazole according to general operating
instructions 7.
Flash point 257-264 C
113
6-[[2-(4-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-hydroxy-2-(4-methylphenyl)-1-
phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 99-102 C
Example 92
6-[[2-(4-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 6-hydroxy-2-(4-methylphenyl)-1-
phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions B.
Flash point 107-109 C
Example 93
6-[[2-(4-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[2-(4-methylphenyl)-i-phenyl-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
'H-NMR (D6-DMSO) : 6 = 1.33-1.49 ppm m (2H); 1.50-1.62 m
(2H); 1.64-1.77 m (2H); 2.22 t (J = 7.5 Hz, 2H); 2.30 s (3H);
3.90 t (J = 7.5 Hz, 2H); 6.62 d (J = 2 Hz, 1H); 6.94 dd (J = 10,
2 Hz, 1H); 7.15 d (J = 8 Hz, 2H); 7.36 d (J = 8 Hz, 2H); 7.40 dd
(J = 8, 1.5 Hz, 2H); 7.52-7.62 m (3H); 7.68 d (J = 10 Hz, 1H).
CA 02396227 2002-07-04 1
114
Example 94
6-[(2-(4-Methylphenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexan-l-
ol
was obtained by reaction of 6-[[2-(4-methylphenyl)-1-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 11.
Flash point 150-152 C
Example 95
6-[[1-Phenyl-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 6-Methoxy-l-phenyl-2-(4-pyridinyl)-1H-benzimidazole
0.4 g of 4-methoxy-N2-phenyl-o-phenylenediamine was
dissolved in 8 ml of N,N-dimethylformamide, and the solution was
mixed with 0.7 g of ethyl-2-ethoxy-l,2-dihydroquinoline-l-
carboxylate and 0.34 g of isonicotinic acid. It was stirred for
16 hours at 100 C, mixed with water after cooling, extracted
three times with ethyl acetate, the combined organic phases were
washed with saturated sodium chloride solution, dried on sodium
sulfate and concentrated by evaporation in a vacuum. After
chromatographic purification on silica gel, the amide was taken
up in 5 ml of 6N aqueous hydrochloric acid and refluxed for 3
hours. After cooling, it was stirred in saturated sodium
bicarbonate solution, extracted three times with ethyl acetate,
the combined extracts were washed with saturated sodium chloride
solution, dried on sodium sulfate and concentrated by evaporation
in a vacuum.
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115
'H-NMR (CDC13): 6 = 3.80 ppm s (3H); 6.66 ppm d (J = 2 Hz,
1H); 7.02 dd (J = 10, 2 Hz, 1H); 7.32-7.38 m (2H); 7.42 dd (J =
8, 1.5 Hz, 2H); 7.54-7.62 m (3H); 7.79 d (J = 10 Hz, 1H); 8.53 d
(broad)(J = 6 Hz, 2H)
b) 6-Hydroxy-l-phenyl-2-(4-pyridinyl)-1H-benzimidazole
was produced by reaction of 6-methoxy-l-phenyl-2-(4-pyridinyl)-
1H-benzimidazole according to general operating instructions 7.
1H-NMR (CD3OD): 6 = 6.52 ppm d (J = 2 Hz, 1H); 6.82 dd (J =
10, 2 Hz, 1H); 7.28-7.33 m (2H); 7.39dd (J = 8, 1.5 Hz, 2H);
7.49-7.57 m (4H); 8.40 d (broad)(J = 6 Hz, 2H).
6-[[1-Phenyl-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was produced by reaction of 6-hydroxy-l-phenyl-2-(4-pyridinyl)-
1H-benzimidazole according to general operating instructions 8.
Flash point 100-103 C
Example 96
6-[[l-Phenyl-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic
acid
was produced by reaction of 6-[[l-phenyl-2-(4-pyridinyl)-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
Flash point 160-162 C
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116
Example 97
6-[(1,2-Diphenyl-5-nitro-3.H-benzimidazol-6-yl)oxy]hexanoic acid
methyl ester
a) 1,2-Diphenyl-6-hydroxy-5-nitro-1H-benzimidazole
b) 1,2-Diphenyl-6-hydroxy-7-nitro-1H-benzimidazole
c) 1,2-Diphenyl-6-hydroxy-5,7-dinitro-1H-benzimidazole
g of 1,2-diphenyl-6-hydroxy-1H-benzimidazole was dissolved
in 45 ml of glacial acetic acid and mixed at 10-15 C drop by drop
with a solution that consists of 1.67 g of potassium nitrite in
ml of water. It was allowed to stir for 2 hours in an ice
bath and then for 2 hours at 20 C, the reaction mixture was
concentrated by evaporation in a vacuum and purified by
chromatography on silica gel.
a) 1H-NMR (CDC13): 6 = 6.83 ppm s (1H); 7.25-7.44 m (5H);
7.52-7.60 m (5H); 8.66 s (1H); 10.78 s (1H).
b) 1H-NMR (D6-DMSO): 6 = 7.05 ppm d (J = 10 Hz, 1H); 7.30-
7.53 m (10H); 7.82 d (J = 10 Hz, 1H); 10.83 s (MH).
c) 1H-NMR (D6-DMSO) : 6 = 7.32-7.58 ppm m (10H) ; 8.67 s
(1H).
6-[(1,2-Diphenyl-5-nitro-lH-benzimidazol-6-yl)oxy]hexanoic
acid methyl ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-5-nitro-lH-
benzimidazole with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
Flash point 123 C
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117
Example 98
6-[(1,2-Diphenyl-5-nitro-iH-benzimidazol-6-yl)oxy]hexanoic acid
isopropyl ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-5-nitro-lH-
benzimidazole with 6-bromohexanoic acid isopropyl ester according
to general operating instructions 8.
Flash point 115-117 C
Example 99
6-[(1,2-Diphenyl-7-nitro-lH-benzimidazol-6-yl)oxy]hexanoic acid
methyl ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-7-nitro-1H-
benzimidazole with 6-bromohexanoic acid methyl ester according to
general operating instructions 8.
Flash point 110-112 C
Example 100
6-[(1,2-Diphenyl-7-nitro-lH-benzimidazol-6-yl)oxy]hexanoic acid
isopropyl ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-5-nitro-iH-
benzimidazole with 6-bromohexanoic acid isopropyl ester according
to general operating instructions 8.
Flash point 88 C
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118
Example 101
6-[(7-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid
methyl ester
340 mg of 6-[(1,2-diphenyl-7-nitro-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester was hydrogenated in ethanol
with Raney nickel in an autoclave at 50 C and at normal pressure.
After hydrogen absorption ended, catalyst was filtered out and
concentrated by evaporation in a vacuum.
Flash point 113-115 C
Example 102
6-[(7-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid
isopropyl ester
was obtained analogously to the instructions indicated in Example
101 by reaction of 6-[(1,2-diphenyl-7-nitro-1H-benzimidazol-6-
yl)oxy]hexanoic acid isopropyl ester.
1H-NMR (CDC13): 6 = 1.22 ppm d (J = 7.5 Hz, 6H) ; 1.43-1.88
m (6H); 2.30 t (J = 7.5 Hz, 2H); 4.04 t (J = 7.5 Hz, 2H); 5.00 sp
(J = 7.5 Hz, 1H); 6.97 d (J = 7.5 Hz, 1H); 7.20-7.33 m (4H);
7.42-7.53 m (M).
Example 103
6-[(5,7-Dinitro-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid methyl ester
was obtained by reaction of 5,7-dinit.ro-1,2-diphenyl-6-hydroxy-
1H-benzimidazole with 6-bromohexanoic acid methyl ester according
to general operating instructions 8.
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119
Flash point 88-91 C
Example 104
6-[(5,7-Dinitro-1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester
was obtained by reaction of 5,7-dinitro-1,2-diphenyl-6-hydroxy-
1H-benzimidazole with 6-bromohexanoic acid isopropyl ester
according to general operating instructions 8.
Flash point 92-93 C
Example 105
6-[[5-(Acetylamino)-1,2-diphenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 5-Fluoro-2,4-dinitrophenol
0.41 g of 1,3-difluoro-4,6-dinitrobenzene was dissolved in 8
ml of 0.5 N aqueous sodium hydroxide solution and refluxed for 2
hours. After cooling, it was diluted with water and extracted
three times with diethyl ether. The aqueous phase was made
acidic by adding iN hydrochloric acid and extracted with diethyl
ether. The organic phase was dried on sodium sulfate and
concentrated by evaporation in a vacuum.
IH-NMR (CDC13) b = 7.10 ppm d (J = 12 Hz, 1H) ; 9.03 d (J =
8 Hz, 1H); 11.10 s (1H).
b) 2,4-Dinitro-5-hydroxydiphenylamine
100 Al of aniline was added to the suspension that consists
of 50 mg of 5-fluoro-2,4-dinitrophenol in 0.5 ml of ethanol, it
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was stirred for 30 minutes and then allowed to stand for 15
hours. It was suctioned off, the solid was washed with IN
aqueous hydrochloric acid and dried in a vacuum.
1H-NMR (CDC13): 6 = 6.58 ppm s (1H); 7.31 d (J = 10 Hz,
2H); 7.39 dd (J = 10, 10 Hz, 1H); 7.51 dd (J = 10, 10 Hz, 2H);
9.20 s (1H); 9.90 s (broad)(1H); 10.97 s (broad)(1H).
c) Acetic acid-(2,4-dinitro-5-phenylamino)phenyl ester
0.11 ml of acetic acid anhydride was added to 275 mg of 2,4-
dinitro-5-hydroxydiphenylamine in 1 ml of pyridine, and it was
allowed to stir for 30 minutes in an ice bath and then for 1 more
hour at 20 C. After dilution with ethyl acetate, it was washed
three times with ice-cold IN aqueous hydrochloric acid, once with
saturated potassium bicarbonate solution and once with saturated
sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum.
'H-NMR (CDC13): 6 = 2.34 ppm s (3H); 6.80 s (1H); 7.32 d (J
Hz, 2H); 7.40 dd (J = 10, 10 Hz, 1H); 7.52 dd (J = 10.10 Hz,
2H) ; 9.21 s (1H) ; 9.95 s (broad) (1H) .
d) Acetic acid-(1,2-diphenyl-6-hydroxy-lH-benzimidazol-5-
yl) amide
was obtained by reaction of acetic acid-(2,4-dinitro-5-
phenylamino)phenyl ester according to general operating
instructions 1 and subsequent reaction with trimethyl
orthobenzoate according to general operating instructions 3.
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'H-NMR (CDC13) ; b = 2.26 ppm s (3H) ; 6.88 s (1H) ; 7.22-7.36
m (5H) ; 7.42-7.53 m (5H) ; 7.61 s (1H) ; 8.43 s (broad)(1H)
6-[[5-(Acetylamino)-1,2-diphenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of acetic acid-(1,2-diphenyl-6-hydroxy-
1H-benzimidazol-5-yl)amide with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 128-130 C
Example 106
6-[(5-Amino-1,2-diphenyl-3LH-benzimidazol-6-yl)oxy]hexanoic acid
isopropyl ester
was obtained by reaction of 6-[(1,2-diphenyl-5-nitro-1H-
benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester according to
general operating instructions 1.
1H-NMR (CDC13) 6 = 1.23 ppm d (J = 7.5 Hz, 6H); 1.47-1.90
m (6H); 2.32 t (J = 7.5 Hz, 2H); 3.95 t (J = 7.5 Hz, 2H); 5.02 sp
(J = 7.5 Hz, 1H); 6.60 s (1H); 7.20 s (1H); 7.22-7.33 m (5H);
7.43-7.58 m (5H).
Example 107
6- [ [5- [ [ (4-Bromophenyl) sulfonyl] amino] -1, 2-diphenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 4-bromobenzenesulfonic acid chloride.
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Flash point 173-175 C
Example 108
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid
methyl ester
was obtained by reaction of 6-[(1,2-diphenyl-5-nitro-lH-
benzimidazol-6-yl)oxy]hexanoic acid methyl ester according to
general operating instructions 1.
1H-NMR (CDC13): 6 = 1.48-1.88 ppm (6H); 2.36 t (J = 7.5 Hz,
2H, CH2=CO); 3.67 s (3H); 3.94 t (J = 7.5 Hz, 2H); 6.60 s (1H);
7.21 s (1H); 7.22-7.35 m (5H); 7.43-7.59 m (5H).
Example 109
6- [ [5- I [ (4-Chlorophenyl) sulfonyl] amino] -1, 2-diphenyl-lH-
benzimidazol-6-ylloxylhexanoic acid methyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxylhexanoic
acid methyl ester was reacted according to general operating
instructions 13 with 4-chlorobenzenesulfonic acid chloride.
Flash point 157-159 C
Example 110
6- [ [5- [ I (4-Chlorophenyl) sulfonyl] amino] -1, 2-diphenyl-lH-
benzimidazol-6-ylloxylhexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 4-chlorobenzenesulfonic acid chloride.
Flash point 158-159 C
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Example 111
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1, 2-diphenyl-iH-
benzimidazol-6-yl]oxy]hexanoic acid
was obtained by reaction of 6-[[5-[[(4-chlorophenyl)sulfonyl]-
amino]-1,2-diphenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl
ester according to general operating instructions 9.
Flash point 201-203 C
Example 112
6-[[1,2-Diphenyl-5-[[(3-methylphenyl) sulfonyl] amino]-iH-
benzimidazol-6-ylloxy]-hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 3-methylbenzenesulfonic acid chloride.
Flash point 149-151 C
Example 113
6- [ [1, 2-Diphenyl-5- [ [ (4-methylphenyl) sulfonyl] amino] -1H-
benzimidazol-6-yl]oxyl-hexanoic acid isopropyl ester
6-[(5-Amino-l,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 4-methylbenzenesulfonic acid chloride.
Flash point 139-141 C
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Example 114
6- [ [1, 2-Diphenyl-5- [ [ (4-methoxyphenyl) sulfonyl] amino] -iH-
benzi.midazol-6-yl]oxy]-hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 4-methoxybenzenesulfonic acid chloride.
1H-NMR (CDC13) 6 = 1.25 ppm d (J = 7.5 Hz, 6H); 1.35-1.45
m (2H); 1.59-1.73 m (4H); 2.30 t (J = 7.5 Hz, 2H); 3.72 t (J =
7.5 Hz, 2H); 3.80 s (3H); 5.02 sp (J = 7.5 Hz, 1H); 6.50 s (1H);
6.85 d (J = 10 Hz, 2H); 6.99 s (1H); 7.25-7.35 m (5H); 7.45-7.52
m (5H); 7.74 d (J = 10 Hz, 2H); 7.99 s (1H).
Example 115
6- [ [1, 2-Diphenyl-5- [ [ [ (4-trifluoromethyl) phenyl] sulfonyl] amino] -
1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 4-(trifluoromethyl)benzenesulfonic acid
chloride.
Flash point 170-171 C
Example 116
6- [ [5- [ [ [4- (Acetylamino)phenyl] sulfonyl] amino] -1, 2-diphenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
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instructions 13 with 4-(acetylamino)benzenesulfonic acid
chloride.
Flash point 100-102 C
Example 117
6- [ [5- [ [Bis (3-chlorophenyl) sulfonyl] amino] -1, 2-Biphenyl-iH-
benzimidazol-6-yl]oxy]-hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with 3-chlorobenzenesulfonic acid chloride.
Flash point 163-167 C
Example 118
6-[[1,2-Diphenyl-5-[(propylsulfonyl)amino]-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted according to general operating
instructions 13 with propanesulfonic acid chloride.
Flash point 126-128 C
Example 119
6-[[5-[(Benzylsulfonyl)amino]-1,2-diphenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic
acid isopropyl ester was reacted with benzenemethanesulfonic acid
chloride according to general operating instructions 13.
Flash point 137-138 C
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Example 120
4-[(1,2-Diphenyl-1H-benzimidazol-6-yl]oxylmethylbenzoic acid
methyl ester
was produced by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 4-(bromomethyl)-benzoic acid methyl ester
according to general operating instructions 8.
Flash point 180-184 C
Example 121
4-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]methylbenzoic acid
was produced by reaction of 4-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]methylbenzoic acid methyl ester according to general
operating instructions 9.
1H-NMR (D6-DMSO) : 6 = 5.12 ppm s (2H) ; 6.76 d (J = 2 Hz,
1H); 7.04 dd (J = 10, 2 Hz, 1H); 7.30-7.63 m (12H); 7.70 d (J =
Hz, 1H); 7.89 d (J = 8 Hz, 2H).
Example 122
4-([1-(3-Methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]methylbenzoic acid methyl ester
was produced by reaction of 6-hydroxy-l-(3-methylphenyl)-2-
phenyl-1H-benzimidazole with 4-(bromomethyl)benzoic acid methyl
ester according to general operating instructions 8.
Flash point 138-142 C
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Example 123
4-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]methylbenzoic acid methyl ester
was produced by reaction of 6-hydroxy-l-(4-methylphenyl)-2-
phenyl-1H-benzimidazole with 4-(bromomethyl)benzoic acid methyl
ester according to general operating instructions 8.
Flash point 145-148 C
Example 124
2- [2 - [ (1, 2 -Diphenyl-lH-benzimidazol- 6 -yl) oxy] ethoxy] acetic acid-
tert-butyl ester
0.2 g of [(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]ethan-l-ol
was suspended in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran.
0.1 ml of bromoacetic acid-tert-butyl ester, 13 mg of
tetrabutylammonium hydrogen sulfate, and 1.45 ml of 32% sodium
hydroxide solution were added to it, and it was allowed to stir
for 48 hours. Another 0.1 ml of bromoacetic acid-tert-butyl
ester and 13 mg of tetrabutylammonium hydrogen sulfate were
added, and the mixture was left for 48 hours in an ultrasound
bath. Then, it was diluted with water and extracted three times
with toluene. The combined organic phases were washed with water
and saturated sodium chloride solution, dried on sodium sulfate
and concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
'H-NMR (CDC13) : 6 = 1.43 ppm s (9H) ; 3.91 t (J = 6 Hz,.2H);
4.10 s (2H); 4.17 t (J = 6 Hz, 2H); 6.75 d (J = 2 Hz, 1H); 7.00
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dd (J = 10, 2 Hz, 1H); 7.24-7.36 m (5H); 7.45-7.56 m (5H); 7.76 d
(J = 10 Hz, 1H).
Example 125
2-[2-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid
50 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]ethoxy]acetic acid-tent-butyl ester was dissolved in 0.5
ml of trifluoroacetic acid and stirred for 48 hours. Then, it
was diluted with water and extracted three times with ethyl
acetate. The combined organic phases were washed with saturated
sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
Flash point 134-136 C
Example 126
2-[2-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid
methyl ester
35 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]ethoxy]acetic acid was dissolved in 0.4 ml of N,N-
dimethylformamide and mixed with 29 mg of cesium carbonate and 50
Al of methyl iodide. It was stirred for 20 hours, then
concentrated by evaporation in a vacuum and chromatographed on
silica gel.
1H-NMR (CDC13): 6 = 3.73 ppm s (3H); 3.93 t (J = 6 Hz, 2H);
4.18 t (J = 6 Hz, 2H); 4.25 s (2H); 6.73 d (J = 2 Hz, 1H); 7.00
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dd (J = 10, 2 Hz, 1H); 7.25-7.42 m (5H); 7.46-7.58 m (5H); 7.77 d
(J = 10 Hz, 1H).
Example 127
3-[2-[(1,2-Diphenyl-iH-benzimidazol-6-yl)oxylethoxylpropanoic
acid-tert-butyl ester
0.2 g of [(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]ethan-l-ol
was suspended in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran.
60 Al of acrylic acid-tert-butyl ester, 13 mg of
tetrabutylammonium hydrogen sulfate, and 1.45 ml of 32% sodium
hydroxide solution were added to it, and it was allowed to stir
for 48 hours. Another 60 Al of acrylic acid-tart-butyl ester and
13 mg of tetrabutylammonium hydrogen sulfate were added, and the
mixture was left for 48 hours in an ultrasound bath. Then, it
was diluted with water and extracted three times with toluene.
The combined organic phases were washed with water and saturated
sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
1H-NMR (CDC13) : 6 = 1.45 ppm s (9H) ; 2.52 t (J = 8 Hz, 2H) ;
3.73-3.84 m (4H); 4.10 t (J = 6 Hz, 2H); 6.72 d (J = 2 Hz, 1H);
6.99 dd (J = 10, 2 Hz, 1H); 7.22-7.38 m (5H); 7.45-7.57 m (5H);
7.75 d (J = 10 Hz, 1H).
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Example 128
3-[2-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]propanoic
acid
50 mg of 3-[2-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]ethoxy]propanoic acid-tert-butyl ester was dissolved in
0.5 ml of trifluoroacetic acid and stirred for 15 hours. Then,
it was diluted with water and extracted three times with ethyl
acetate. The combined organic phases were washed with saturated
sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
1H-NMR (D6-DMSO): 6 = 2.26 ppm t (J = 8 Hz, 2H); 3.60-3.70
m (4H); 3.98-4.06 m (2H); 6.65 d (J = 2 Hz, 1H); 6.94 dd (J = 10,
2 Hz, 1H); 7.30-7.62 m (10H); 7.68 d (J = 10 Hz, 1H).
Example 129
3- [2 - [ (1, 2 -Diphenyl- lH-benzimidazol- 6 -yl) oxy] ethoxy] propanoic
acid methyl ester
35 mg of 3-[2-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]ethoxy]propanoic acid was dissolved in 0.4 ml of N,N-
dimethylformamide, mixed with 28 mg of cesium carbonate and 50 l
of methyl iodide and stirred for 30 hours. Then, it was diluted
with water and extracted three times with ethyl acetate. The
combined organic phases were washed with saturated sodium
chloride solution, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue was chromatographed on
silica gel.
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Flash point 91-93 C
Example 130
3-[3-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]propoxy]propanoic
acid-tert-butyl ester
0.2 g of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxylpropan-l-
ol was suspended in 1.7 ml of toluene and 0.7 ml of
tetrahydrofuran. 60 Al of acrylic acid-tert-butyl ester, 13 mg
of tetrabutylammonium hydrogen sulfate, and 1.47 ml of 32% sodium
hydroxide solution were added to it, and it was allowed to stir
for 48 hours. Another 60 Al of acrylic acid-tert-butyl ester and
13 mg of tetrabutylammonium hydrogen sulfate were added, and the
mixture was left for 48 hours in an ultrasound bath. Then, it
was diluted with water and extracted three times with toluene.
The combined organic phases were washed with water and saturated
sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
Flash point 95-98 C
Example 131
(E/Z)-5-(1,2-Diphenyl-1H-benzimidazol-6-yl)pent-4-enoic acid
methyl ester
a) 1,2-Diphenyl-6-methyl-lH-benzimidazole
5.1 g of 5-methyl-2-nitrodiphenylamine was hydrogenated in
55 ml of ethanol according to general operating instructions 1.
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The crude product was reacted with trimethyl orthobenzoate
according to general operating instructions 3.
Flash point 134-136 C
b) 1,2-Diphenyl-1H-benzimidazole-6-carbaldehyde
1 g of 1,2-diphenyl-6-methyl-1H-benzimidazole was suspended
in 31 ml of 40% sulfuric acid and mixed with 13.5 g of cerium
ammonium nitrate. It was allowed to stir for 2.5 hours at 80 C,
cooled to 20 C, and carefully stirred into saturated aqueous
sodium bicarbonate solution. The mixture was extracted three
times with ethyl acetate, the combined extracts were washed with
saturated aqueous sodium chloride solution, dried on sodium
sulfate solution and evaporated to the dry state in a vacuum.
The residue was chromatographed on silica gel.
'H-NMR (CDC13) : 6 = 7.30-7.42 ppm m (5H); 7.50-7.66 m (5H);
7.81 d (J = 2 Hz, 1H); 7.89 dd (J = 8, 2 Hz, 1H); 8.00 d (J = 8
Hz, 1H) ; 10.05 s (1H).
(E/Z)-5-(1,2-Diphenyl-lH-benzimidazol-6-yl)pent-4-enoic acid
methyl ester
was obtained by reaction of 1,2-diphenyl-1H-benzimidazole-6-
carbaldehyde according to general operating instructions 12 with
3-carboxypropyltriphenylphosphonium bromide.
1H-NMR (CDC13): 6 = 2.40-2.71 ppm m (4H); 3.68 (3.66) at s
(3H) each; 5.56-5.64 (6.12-6.22) at m (1H) each; 6.50 d (J = 18
Hz, 1H); 6.58 d (broad) (J = 12 Hz, 1H); 7.12 (7.15) at s
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(broad)(1H) each; 7.25-7.40 m (6H); 7.45-7.62 m (5H); 7.80 (7.83)
at d (J = 8 Hz, 1H) each.
Example 132
E-5-(1,2-Diphenyl-lH-benzimidazol-6-yl)pent-4-enoic acid
was obtained by reaction of (E/Z)-5-(1,2-diphenyl-lH-
benzimidazol-6-yl)pent-4-enoic acid methyl ester according to
general operating instructions 9.
1H-NMR (CD3OD): 6 = 2.26-2.43 ppm m (4H); 6.10-6.21 m (1H);
6.45 d (J = 18 Hz, 1H); 7.08 s (1H); 7.22-7.52 m (11H); 7.59-d (J
8 Hz, 1H).
Example 133
5-(1,2-Diphenyl-lH-benzimidazol-6-yl)pentanoic acid methyl ester
was obtained by reaction of (E/Z)-5-(l,2-diphenyl-lH-
benzimidazol-6-yl)pent-4-enoic acid methyl ester according to
general operating instructions 1.
1H-NMR -(CDC13) : 6 = 1.63-1.72 ppm m (4H) ; 2.30-2.39 m (2H) ;
2.68-2.77 m (2H); 3.65 s (3H); 7.04 s (broad)(1H); 7.17 dd (J =
8, 2 Hz, 1H); 7.25-7.38 m (5H); 7.45-7.60 m (5H); 7.79 d (J = 8
Hz, 1H).
Example 134
5-(1,2-Diphenyl-lH-benzimidazol-6-yl)pentanoic acid
was obtained by reaction of 5-(1,2-diphenyl-lH-benzimidazol-6-
yl)pentanoic acid methyl ester according to general operating
instructions 9.
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Flash point 192-193 C
Example 135 (E/Z)-6-(1,2-Diphenyl-iH-benzimidazol-6-yl)hex-5-
enoic acid methyl ester
was obtained by reaction of 1,2-diphenyl-lH-benzimidazole-6-
carbaldehyde according to general operating instructions 12 with
4-carboxybutyltriphenylphosphonium bromide.
1H-NMR (CDC13) : 6 = 1.72-1.88 ppm m (2H) ; 2.20-2.42 m (4H) ;
3.65 (3.67) at s (3H, CH3) each; 5.57-5.68 (6.10-6.20) at m (1H)
each; 6.48 d (J = 18 Hz, 1H); 6.56 d (broad)(J = 12 Hz, 1H); 7.12
(7.16) at s (broad)(1H) each; 7.25-7.38 m (6H); 7.45-7.60 m (5H);
7.80 (7.84) at d (J = 8 Hz, 1H) each.
Example 136 (E/Z)-6-(1,2-Diphenyl-lH-benzimidazol-6-yl)hex-5-
enoic acid
was obtained by reaction of (E/Z)-6-(1,2-diphenyl-lH-
benzimidazol-6-yl)hex-5-enoic acid methyl ester according to
general operating instructions 9.
1H-NMR (CDC13) : 6 = 1.74-1.89 ppm m. (2H) ; 2.22-2.43 m (4H) ;
5.58-5.68 (6.10-6.22) at m (1H) each; 6.47 d (J = 18 Hz, 1H);
6.55 d (broad) (J = 12 Hz, 1H) ; 7. 11 (7. 14)' at s (broad) (1H)
each; 7.25-7.40 m (6H); 7.48-7.59 m (SH) ; 7.80 (7.85) at d (J = 8
Hz, 1H) each.
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Example 137 6-(1,2-Diphenyl-1H-benzimidazol-6-yl)hexanoic acid
methyl ester
was obtained by reaction of (E/Z)-6-(1,2-diphenyl-lH-
benzimidazol-6-yl)hex-5-enoic acid methyl ester according to
general operating instructions 1.
1H-NMR (CDC13) : 6 = 1.32-1.43 ppm m (2H) ; 1.62-1.74 m (4H) ;
2.31 t (J = 7.5 Hz, 2H); 2.72 t (J = 7.5 Hz, 2H); 3.56 s (3H);
7.02 s (broad)(1H); 7.18 dd (J = 8, 2 Hz, 1H); 7.27-7.38 m (5H);
7.45-7.60 m (5H); 7.80 d (J = 8 Hz, 1H).
Example 138
6-(1,2-Diphenyl-1H-benzimidazol-6-yl)hexanoic acid
was obtained by reaction of 6-_(1,2-diphenyl-1H-benzimidazol-6-
yl)hexanoic acid methyl ester according to general operating
instructions 9.
1H-NMR (CDC13) : 6 = 1.30-1.45 ppm m (2H) ; 1.54-1.74 m (4H) ;
2.32 t (J = 7.5 Hz, 2H); 2.70 t (J = 7.5 Hz, 2H); 7.02 s
(broad)(1H); 7.20 dd (J = 8, 2 Hz, 1H); 7.25-7.38 m (5H); 7.42-
7.60 m (5H); 7.81 d (J = 8 Hz, 1H).
Example 139 (E/Z)-7-(1,2-Diphenyl-1H-benzimidazol-6-yl)hept-6-
enoic acid methyl ester
was obtained by reaction of 1,2-diphenyl-1H-benzimidazole-6-
carbaldehyde according to general operating instructions 12 with
5-carboxypentyltriphenylphosphonium bromide.
'H-NMR (CDC13): 6 = 1.43-1.55 ppm m (2H); 1.58-1.72 m (2H);
2.18-2.38 m (4H); 3.65 (3.66) at s (3H, CH3) each; 5.58-5.68
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(6.12-6.22) at m (1H) each; 6.45 d (J = 18 Hz, 1H); 6.54 d
(broad) (J = 12 Hz, 1H); 7.12 (7.14) at s (broad)(1H) each; 7.26-
7.40 m (6H); 7.48-7.60 m (5H); 7.80 (7.83) at d (J = 8 Hz, 1H)
each.
Example 140
(E/Z)-7-(1,2-Diphenyl-3LH-benzimidazol-6-yl)hept-6-enoic acid
was obtained by reaction of (E/Z)-7-(1,2-diphenyl-1H-
benzimidazol-6-yl)hept-6-enoic acid methyl ester according to
general operating instructions 9.
1H-NMR (D6-DMSO): 6 = 1.40-1.60 ppm m (4H); 2.14-2.28 m
(4H); 6.18-6.30 m (1H); 6.50 d (J = 18 Hz, 1H); 7.07 (7.12) at s
(broad)(1H) each; 7.32-7.64 m (11H); 7.70 (7.78) at d (J = 8 Hz,
1H) each; 12.00 s (broad)(1H).
Example 141
7-(1,2-Diphenyl-lH-benzimidazol-6-yl)heptanoic acid methyl ester
was obtained by reaction of (E/Z)-7-(1,2-diphenyl-lH-
benzimidazol-6-yl)hept-6-enoic acid methyl ester according to
general operating instructions 1.
1H-NMR (CDC13): 6 = 1.30-1.42 ppm m (4H); 1.55-1.70 m (4H);
2.30 t (J = 7.5 Hz, 2H); 2.68 t (J = 7.5 Hz, 2H); 3.56 s (3H);
7.02 s (broad)(1H); 7.18 dd (J = 8, 2 Hz, 1H); 7.28-7.35 m (5H);
7.45-7.58 m (5H); 7.79 d (J = 8 Hz, 1H).
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Example 142 7-(1,2-Diphenyl-1H-benzimidazol-6-yl)heptanoic acid
was obtained by reaction of 7-(1,2-diphenyl-1H-benzimidazol-6-
yl)heptanoic acid methyl ester according to general operating
instructions 9.
Flash point 99-103 C
Example 143
N-(1,2-Diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide
Example 144 N-(Phenylsulfonyl)-N-(1,2-diphenyl-lH-benzimidazol-
5-yl) benzenesulfonamide
a) 5-Amino-1,2-diphenyl-iH-benzimidazole
2,4-Diaminodiphenylamine is reacted with trimethyl
orthobenzoate according to general operating instructions 3.
'H-NMR (CDC13) : 6 = 6.70 ppm dd (J = 7.5, 2 Hz, 1H) ; 7.06 d
(J = 7.5 Hz, 1H); 7.18 d (J = 2 Hz, 1H); 7.28-7.60 m (10H).
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with
benzenesulfonic acid chloride according to general operating
instructions 13.
143-: Flash point 196-205 C
144: 'H-NMR (CDC13) : 6 = 6.94 ppm dd (J = 7.5, 2 Hz, 1H) ;
7.20 d (J = 2 Hz, 1H); 7.26-8.04 m (21H).
Example 145 3-Chloro-N-(1,2-diphenyl-1H-benzimidazol-5-
yl) benzenesulfonamide
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Example 146 N-[(3-Chlorophenyl)sulfonyl]-N-(1,2-diphenyl-iH-
benzimidazol-5-yl)-(3-chlorobenzene) sulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 3-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
145: Flash point 160-162 C
146: 1H-NMR (CDC13) : 6 = 6.93 ppm dd (J = 7.5, 2 Hz, 1H)
7.25 d (J = 2 Hz, 1H); 7.28-7.57 m (13H); 7.66 d (broad)(2H);
7.90 d (broad) (2H) ; 8.00 d (broad) (2H) .
Example 147 4-Chloro-N-(1,2-diphenyl-lH-benzimidazol-5-
yl) benzenesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
1H-NMR (CDC13) : 6 6.86 ppm s (broad) (1H) ; 7.11 d (J =
7.5, 2 Hz, 1H); 7.17 d (J = 2 Hz, 1H); 7.25-7.55 m (12H); 7.70 d
(J = 10 Hz, 2H).
Example 148 4-Bromo-N-(1,2-diphenyl-lH-benzimidazol-5-
yl) benzenesulfonamide
Example 149 N-(4-Bromophenylsulfonyl)-N-(1,2-diphenyl-lH-
benzimidazol- 5-yl)-4-bromobenzenesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-
bromobenzenesulfonic acid chloride according to general operating
instructions 13.
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148: Flash point 135-139 C
149: 'H-NMR (CDC13): 6 = 6.90 ppm dd (J = 7.5, 2 Hz, 1H);
7.23 d (J = 2 Hz, 1H); 7.28-7.43 m (11H); 7.72 d (J = 10 Hz, 2H);
7.86 d (J = 10 Hz, 2H).
Example 150 4-(Trifluoromethyl)-N-(1,2-diphenyl-lH-benzimidazol-
5-yl) benzenesulfonamide
Example 151 N-(1,2-Diphenyl-lH-benzimidazol-5-yl)-N-[(3-
trifluoromethyl) phenylsulfonyl] - (3-
trifluoromethyl) benzenesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with (3-
trifluoromethyl)benzenesulfonic acid chloride according to
general operating instructions 13.
150: Flash point 116-121 C
151: Flash point 238-241 C
Example 152 3-Methyl-N-(1,2-diphenyl-lH-benzimidazol-5-
yl)benzenesulfonamide
Example 153 N- (1, 2-Diphenyl-1H-benzimidazol-5-yl) -N- (3-
methyiphenylsulfonyl) -3 -methylbenzenesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 3-
methylbenzenesulfonic acid chloride according to general
operating instructions 13.
152: Flash point 192-195 C
153: Flash point 173-176 C
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Example 154 4-Methyl-N-(1,2-Diphenyl-iH-benzimidazol-5-
yl) benzenesulfonamide
Example 155 N-(1,2-Diphenyl-lH-benzimidazol-5-yl)-N-(4-
methylphenylsulfonyl)-4-methyl-benzenesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-
methylbenzenesulfonic acid chloride according to general
operating instructions 13.
154: 1H-NMR (CDC13) : 6 = 2.38 ppm s (3H) ; 6.77 s
(broad)(1H); 7.14-7.55 m (14H); 7.66 d (J = 10 Hz, 2H).
155: Flash point 234-236 C
Example 156
4-Methoxy-N-(1,2-Diphenyl-lH-benzimidazol-5-yl)benzenesulfonamide
Example N-(1,2-Diphenyl-lH-benzimidazol-5-yl)-N-(4-
methoxyphenylsulfonyl)-4-methoxybenzenesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-
methoxybenzenesulfonic acid chloride according to general
operating instructions 13.
156: 1H-NMR (CDC13) : 6 = 3.82 ppm s (3H) ; 6.78 s
(broad)(1H, H-4); 6.88 d (J = 7.5 Hz, 1H); 7.14 d (J = 1.5 Hz,
1H); 7.28-7.55 m (12H); 7.72 d (J = 8 Hz, 2H).
157: 1H-NMR (CDC13) : 6 = 3.90 ppm s (6H) ; 6.93 dd (J =
7.5, 2 Hz, 1H); 7.00 d (J = 10 Hz, 4H); 7.06 d (J = 2 Hz, 1H);
7.30-7.58 m (11H); 7.93 d (J = 10 Hz, 4H).
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Example 158 N-(1,2-Diphenyl-iH-benzimidazol-5-
yl) propanesulfonamide
Example 159 N-(1,2-Diphenyl-lH-benzimidazol-5-yl)-N-
(propylsulfonyl)-propanesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with
propanebenzenesulfonic acid chloride according to general
operating instructions 13.
158: 1H-NMR (CDC13/D6-DMSO): 6 = 0.80 ppm t (J = 7.5 Hz,
3H); 1.65 m (2H); 2.82 m (2H); 6.95 d (J = 7.5 Hz, 1H); 7.08 dd
(J = 7.5, 2 Hz, 1H); 7.10-7.40 m (10H); 7.61 d (J = 2 Hz, 1H);
9.05 s (broad)(1H, NH).
159: 1H-NMR (CDC13): 6 = 1.08 ppm t (J = 7.5 Hz, 3H); 1.12
t (J = 7.5 Hz, 3H); 2.00 m (4H); 3.60 m (4H); 7.25-7.63 m (13H).
Example 160
N-(1,2-Diphenyl-lH-benzimidazol-5-yl)benzenemethanesulfonamide
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with
benzenemethanesulfonic acid chloride according to general
operating instructions 13.
Flash point 185-188 C
Example 161
6-[[1,2-Diphenyl-iH-benzimidazol-5-yl]aminolhexanoic acid methyl
ester
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Example 162
6-[N-(1,2-diphenyl-lH-benzimidazol-5-yl)-N-[(5-methoxycarbonyl)-
pentyl] amino]hexanoic acid methyl ester
207 mg of 6-bromohexanoic acid methyl ester, 138 mg of
potassium carbonate and 150 mg of sodium iodide were added to a
solution of 285 mg of 5-amino-1,2-diphenyl-1H-benz.imidazole in 5
ml of methanol, and it was allowed to stir for 3 days at 20 C.
It was mixed with water, extracted three times with ethyl
acetate, the combined organic phases were dried on sodium sulfate
and concentrated by evaporation in a vacuum. The residue was
chromatographed on silica gel.
161: Flash point 109-113 C
162: 1H-NMR (CDC13): 6 = 1.30-1.43 m (4H); 1.53-1.73 m
(8H); 2.32 t (J = 7.5 Hz, 4H); 3.30 t (J = 7.5 Hz, 4H); 3.68 s
(6H); 6.75 dd (J = 10, 2 Hz, 1H); 7.10 d (J = 10 Hz, 1H); 7.14 d
(J = 2 Hz, 1H); 7.23-7.35 m (5H); 7.42-7.58 m (5H).
Example 163 6-[[1,2-Diphenyl-lH-benzimidazol-5-yl]amino]hexanoic
acid
was obtained-by reaction of 6-[[1,2-diphenyl-lH-benzimidazol-5-
yl]amino]hexanoic acid methyl ester according to general
operating instructions 9.
'H-NMR (D6-DMSO) 6 = 1.35-1.50 ppm m (2H); 1.50-1.68 m
(4H); 2.23 t (J = 7.5 Hz, 2H); 3.05 t (J = 7.5 Hz, 2H); 6.67 dd
(J = 10, 2 HZ, 1H); 6.80 d (J = 2 Hz, 1H); 6.92 d (J = 10 Hz,
1H); 7.30-7.40 m (4H); 7.45-7.62 m (6H).
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Example 164
6-[[2-Phenyl-1-[4-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) (5-Hydroxy-2-nitrophenyl)[(4-(phenylmethoxy)phenyl] amine
1 g of 3-fluoro-4-nitrophenol and 3.8 g of 4-
benzyloxyaniline were stirred for 6.5 hours at 150 C. The batch
was then diluted with dichloromethane. After two cycles of
extraction with 1N aqueous hydrochloric acid and washing with
water, it was extracted twice with 2N aqueous sodium hydroxide
solution. The basic water phase was mixed with ethyl acetate and
1N aqueous hydrochloric acid. After phase separation, the
organic phase was extracted several times with iN aqueous
hydrochloric acid. After the organic phase was washed with
saturated sodium chloride solution, it was dried on sodium
sulfate, concentrated by evaporation in a vacuum, and the residue
was chromatographed on silica gel.
1H-NMR (D6-DMSO) : 6 = 5.14 ppm s (2H) ; 6.23 m (2H) ; 7.10 d
(J = 8 Hz, 2H); 7.26 d (J = 8 Hz, 2H); 7.32-7.52 m (5H); 8.03 d
(J = 8 Hz, 1H); 9.52 s (1H); 10.71 s (1H).
b) 6 - [ [4 -Nitro- 3 - [ [4 - (phenylmethoxy)phenyl] amino] -
phenyl]oxy]hexanoic acid methyl ester
was obtained by reaction of (5-hydroxy-2-nitrophenyl)[(4-
(phenylmethoxy)phenyl] amine with 6-bromohexanoic acid methyl
ester according to general operating instructions 8.
'H-NMR (CDC13) : 6 = 1.37-1.50 m (2H) ; 1.59-1.80 m (4H) ;
2.33 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.83 t (J = 7.5 Hz, 2H);
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5.12 s (2H); 6.24-6.33 m (2H); 7.04 d (J = 8 Hz, 2H); 7.21 d (J =
8 Hz, 2H); 7.32-7.50 m (5H); 8.17 d (J = 8 Hz, 1H); 9.66 s (1H).
6-[[2-Phenyl-l-[4-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reduction of 6-[[4-nitro-3-[[4-
(phenylmethoxy)phenyl] amino] phenyl] oxy] hexanoic acid methyl ester
according to general operating instructions 2 and subsequent
cyclization with trimethyl orthobenzoate according to general
operating instructions 3.
1H-NMR (CDC13): 6 = 1.43-1.58 m (2H); 1.65-1.86 m (4H);
2.35 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.94 t (J = 7.5 Hz, 2H);
5.14 s (2H); 6.64 d (J = 2 Hz, 1H); 6.95 dd (J = 8, 2 Hz, 1H);
7.11 d (J = 8 Hz, 2H); 7.18-7.61 m (12H); 7.74 d (J = 8 Hz, 1H).
Example 165
6-[[2-Phenyl-l-[4-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[2-Phenyl-l-[4-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester was reacted according to
general operating instructions 9.
1H-NMR (D6-DMSO): 6 = 1.36-1.62 m (4H); 1.65-1.78 m (2H);
2.22 t (J = 7.5 Hz, 2H); 3.92 t (J = 7.5 Hz, 2H); 5.18 s (2H);
6.59 d (J = 2 Hz, 1H); 6.92 dd (J = 8, 2 Hz, 1H); 7.20 d (J = 8
Hz, 2H); 7.30-7.54 m (12H); 7.66 d (J = 8 Hz, 1H).
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Example 166
6-[[1-(4-Hydroxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[2-Phenyl-l-[4-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid was reacted according to general operating
instructions 1.
1H-NMR (D6-DMSO) : 6 = 1.37-1.79 m (6H) ; 2.22 t (J = 7.5 Hz,
2H); 3.92 t (J = 7.5 Hz, 2H); 6.60 d (J = 2 Hz, 1H); 6.91 dd (J =
8, 2 Hz, 1H); 6.94 d (J = 8 Hz, 2H); 7.20 d (J = 8 Hz, 2H); 7.36
m (3H) ; 7.52 m (2H) ; 7.63 d (J = 8 Hz, 1H) .
Example 167
6-[[2-Phenyl-l-[3-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
ylloxy]hexanoic acid methyl ester
a) (5 -Hydroxy- 2 -nitrophenyl) [ (3 - (phenylmethoxy) phenyl] amine
1 g of 3-fluoro-4-nitrophenol and 3.81 g of 3-
benzyloxyaniline were stirred for 22 hours at 150 C. Then, it
was taken up in a little dichloromethane and chromatographed
directly on silica gel.
1H-NMR (CDC13) : 6 = 5.10 ppm s (2H) ; 5.82 s (br) (1H) ; 6:27
dd (J = 8, 2 Hz, 1H); 6.48 d (J = 2 Hz, 1H); 6.86 m (3H); 7.28-
7.48 m (5H); 8.15 d (J = 8 Hz, 1H); 9.52 s (br) (1H); 10.71 s
(1H).
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b) 6- [ [4-Nitro-3- [ [3- (phenylmethoxy)phenyl] amino]phenyl] -
oxy]hexanoic acid methyl ester
was obtained by reaction of (5-hydroxy-2-nitrophenyl)[(3-
(phenylmethoxy)phenyl] amine with 6-bromohexanoic acid methyl
ester according to general operating instructions 8.
1H-NMR (CDC13) : S = 1.40-1.53 m (2H) ; 1.61-1.82 m (4H) ;
2.34 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.88 t (J = 7.5 Hz, 2H);
5.10 s (2H); 6.33 dd (J = 8, 2 Hz, 1H); 6.58 d (J = 2 Hz, 1H);
6.83-6.96 m (3H); 7.28-7.49 m (5H); 8.17 d (J,= 8 Hz, 1H); 9.74 s
(br).
6-[[2-Phenyl-l-[3-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reduction of 6-[[4-nitro-3-[[3-
(phenylmethoxy) phenyl] amino] phenyl] oxy] hexanoic acid methyl ester
according to general operating instructions 2 and subsequent
cyclization with trimethyl orthobenzoate according to general
operating instructions 3.
1H-NMR (CDC13): 6 = 1.45-1.60 m (2H); 1.66-1.88 m (4H);
2.35 t (J = 7.5 Hz, 2H); 3.68 s (3H); 3.93 t (J = 7.5 Hz, 2H);
5.02 s (2H); 6.69 d (J = 2 Hz, 1H); 6.90-M (2H); 6.97 dd (J = 8,
2 Hz, 1H); 7.11 ddd (J = 8, 2, 2 Hz, 1H); 7.28-7.46 m (9H); 7.78
d (J = 8 Hz, 1H).
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Example 168
6-[[2-Phenyl-l-[3-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[2-Phenyl-l-[3-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester was reacted according to
general operating instructions 9.
'H-NMR (CDC13): 6 = 1.49-1.62 m (2H); 1.67-1.88 m (4H);
2.39 t (J = 7.5 Hz, 2H); 3.93 t (J = 7.5 Hz, 2H); 5.03 s (2H);.
6.68 d (J = 2 Hz, 1H); 6.91 m (3H); 6.98 dd (J = 8, 2 Hz, 1H);
7.12 ddd (J = 8, 2, 2 Hz, 1H); 7.29-7.47 m (8H); 7.57 d (J = 8
Hz, 2H); 7.81 d (J = 8 Hz, 1H).
Example 169
6-[[1-(3-Hydroxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
6-[[2-Phenyl-l-[3-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid was reacted according to general operating
instructions 1.
1H-NMR (D6-DMSO) 6 = 1.39-1.80 m (6H); 2.23 t (J = 7.5 Hz,
2H); 3.94 t (J = 7.5 Hz, 2H); 6.57 d (J = 2 Hz, 1H); 6.74 dd (J =
2, 2 Hz, 1H); 6.84 dd (J = 8, 2 Hz, 1H); 6.94 m (2H); 7.38 m
(4H) ; 7.53 m (2H) ; 7.66 d (J = 8 Hz, 1H).
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Example 170
6-[[1-(3-Hydroxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
6-[[2-Phenyl-l-[3-(phenylmethoxy)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester was reacted according to
general operating instructions 1.
'H-NMR (D6-DMSO) : 6 = 1.38-1.80 m (6H) ; 2.32 t (J = 7.5 Hz,
2H); 3.59 s (3H); 3.94 t (J = 7.5 Hz, 2H); 6.66 d (J = 2 Hz, 1H);
6.74 dd (J = 2, 2 Hz, 1H); 6.83 dd (J = 8, 2 Hz, 1H); 6.93 dd (J
= 8, 2 Hz, 2H) ; 7.38 m (4H) ; 7.54 m (2H) ; 7.67 d (J = 8 Hz, 1H).
Example 171
6-[[1-(3-Nitrophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid ethyl ester
was obtained by reaction of 6-hydroxy-l-(3-nitrophenyl)-2-
phenylbenzimidazole (DE 4330959) with 6-bromohexanoic acid ethyl
ester according to general operating instructions 8.
Flash point 104-106 C
Example 172
6-[[4-Bromo-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
a) 4-Bromo-6-methoxy-2-phenyl-lH-benzimidazole
36.6 g of 4-amino-3-bromo-5-nitroanisole (J. Chem. Soc.
1966, 1769) was introduced into 750 ml of ethanol and mixed with
19.8 g of iron powder and 126 ml of acetic acid. After being
stirred for 2.5 hours at 55 C, it was mixed with 350 ml of
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dichloromethane and made basic with 2N sodium hydroxide solution.
After filtration on Celite, it was washed with water and
saturated common salt solution and concentrated by evaporation.
The crude phenyldiamine that was thus obtained was reacted with
trimethyl orthobenzoate according to general operating
instructions 3.
Flash point 203-205 C
b) 4-Bromo-6-methoxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole
2.5 g of 4-bromo-6-methoxy-2-phenyl-1H-benzimidazole and
2.24 g of 4-(methylbenzene)boronic acid were stirred with 1.5 g
of anhydrous copper(II) acetate and about 3 g of molecular sieve
in 35 ml of pyridine for 7 hours at 100 C. After dichloromethane
and Celite were added, it was concentrated by evaporation and
chromatographed on silica gel with a hexane/ethyl acetate
mixture.
Flash point 209-210 C
c) 4-Bromo-6-hydroxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole
1.2 g of 4-bromo-6-methoxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole, 6 ml of acetic acid and 6 ml of aqueous
hydrobromic acid (62%) are boiled for 5.5 hours. Then, it is
precipitated with water, and the precipitate is suctioned off.
The latter was then dispersed between ethyl acetate and 2N sodium
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hydroxide solution. After the organic phase was washed with
water, it was concentrated by evaporation.
Flash point 136-137 C
6-[[4-Bromo-1-(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 4-bromo-6-hydroxy-l-(4-methylphenyl)-
2-phenyl-lH-benzimidazole with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
Flash point 136 C
Example 173
6-[[4-Acetyl-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
0.5 g of 4-bromo-6-hydroxy-l-(4-methylphenyl)-2-phenyl-1H-
benzimidazole, 0.37 ml (a-ethoxyvinyl)tributyltin, and 140 mg of
dichlorobis(triphenylphosphine)palladium were stirred in 10 ml of
toluene for 18 hours at 100 C. After cooling, it was stirred
with 2N aqueous hydrochloric acid for 0.25 hour. After phase
separation, the organic phase was washed with water and
concentrated by evaporation. The residue was chromatographed on
silica gel with a hexane/ethyl acetate mixture.
Flash point 114-115 C
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Example 174
6-[[1-(4-Methyiphenyl)-2-phenyl-iH-benzimidazol-5-yl]oxy]hexanoic
acid methyl ester
a) 5-Methoxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazole
16.8 g of 5-methoxy-2-phenyl-1H-benzimidazole (Bull. Sci.
Fac. Chim. Ind. Bologna, 11 1953, 42) and 20.4 g of 4-
(methylbenzene)boronic acid are reacted according to general
operating instructions 14.
1H-NMR (CDC13) : 6 = 2.45 s (3H) ; 3.91 s (3H) ; 6.90 dd (J =
8, 2 Hz, 1H)-, 7.12 d (J = 8 Hz, 1H) ; 7.18 d (J = 8 Hz, 2H) ; 7.25-
7.38 m (6H); 7.57 m (2H).
In addition, 6-methoxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole was obtained.
b) 5-Hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazole
was obtained from 5-methoxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole according to general operating instructions 6.
Flash point 270 C
6-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-5-yl]oxy]hexanoic
acid methyl ester
was obtained from 5-hydroxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole by reaction with 6-bromohexanoic acid methyl ester
according to general operating instructions 8.
'H-NMR (CDC13): 6 = 1.48-1.92 m (6H); 2.38 t (J = 7.5 Hz,
2H); 2.46 s (3H); 3.69 s (3H); 4.06 t (J = 7.5 Hz, 2H); 6.89 dd
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(J = 8, 2 Hz, 1H); 7.11 d (J = 8 Hz, 1H); 7.18 d (J = 8 Hz, 2H);
7.24-7.37 m (6H) ; 7.57 m (2H).
Example 175
6-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-5-yl]oxy]hexanoic
acid
was obtained from 6-[(1-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-5-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
1H-NMR (D6-DMSO) : 6 = 1.41-1.67 m (4H) ; 1.70-1.83 m (2H) ;
2.26 t (J = 7.5 Hz, 2H); 2.43 s (3H); 4.05 t (J = 7.5 Hz, 2H);
6.90 dd (J = 8, 2 Hz, 1H); 7.04 d (J = 8 Hz, 1H); 7.23-7.40 m
(8H) ; 7.52 m (2H) ; 11.92 s (br.) (1H) .
Example 176
6-[[2-Phenyl-l-[4-(thiomethyl)phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester
a) 6- [ [2-Phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl
ester
4.84 g of 2-phenyl-5-hydroxy-1H-benzimidazole (Izv. Akad.
Nauk. SSSR Ser. Chim. 8 1990, 1888) was obtained by reaction with
6-bromohexanoic acid methyl ester according to general operating
instructions 8.
1H-NMR (CDC13) : 6 = 1.43-1.58 m (2H) ; 1.64-1.87 m (4H) ;
2.37 t (J = 7.5 Hz, 2H); 3.69 s (3H); 3.94 t (J = 7.5 Hz, 2H);
6.87 dd (J = 8, 2 Hz, 1H); 7.02 s (br.); 7.40-7.57 m (4H); 8.05 m
(2H).
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6-[[2-Phenyl-l-[4-(thiomethyl)phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with 4-
(thiomethylbenzene)boronic acid according to general operating
instructions 14.
1H-NMR (CDC13) 6 = 1.48-1.61 m (2H) ; 1.66-1.92 m (4H)
2.36 t (J = 7.5 Hz, 2H); 2.54 s (3H); 3.68 s (3H); 4.05 t (J =
7.5 Hz, 2H); 6.90 dd'(J = 8, 2 Hz, 1H); 7.11 d (J = 8 Hz, 1H);
7.22 d (J = 8 Hz, 2H); 7.27-7.49 m (6H); 7.57 m (2H).
Example 177
6-[[2-Phenyl-l-[(4-thiomethyl)phenyl]-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with 4-
(thiomethylbenzene)boronic acid according to general operating
instructions 14.
'H-NMR (CDC13) : 6 = 1.45-1.57 m (2H) ; 1.62-1.86 m (4H) ;
2.44 t (J = 7.5 Hz, 2H); 2.56 s (3H); 3.66 s (3H); 3.93 t (J =
7.5 Hz, 2H); 6.66 d (J = 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H);
7.18-7.39 m (7H); 7.54 m (2H); 7.73 d (J = 8 Hz, 1H).
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Example 178
6-[[2-Phenyl-l-(3-thienyl)-1H-benzimidazol-5-yl]oxy]hexanoic acid
methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with thiophene-3-boronic acid
according to general operating instructions 14.
1H-NMR (CDC13) : 6 = 1.48-1.62 m (2H) ; 1.66-1.92 m (4H) ;
2.47 t (J = 7.5 Hz, 2H); 3.68 s (3H); 4.04 t (J = 7.5 Hz, 2H);
6.93 dd (J = 8, 2 Hz, 1H); 6.98 dd (J = 5, 1 Hz, 1H); 7.18 d (J =
8 Hz, 1H); 7.28 dd. (J = 3, 1 Hz, 1H); 7.30-7.40 m (4H); 7.46 dd
(J = 5, 3 Hz, 1H) ; 7.60 m (2H).
Example 179 6-[[2-Phenyl-l-(3-thienyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with thiophene-3-boronic acid
according to general operating instructions 14.
1H-NMR (CDC13) : 6 = 1.45-1.58 m (2H) ; 1.64-1.87 m (4H)
2.35 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.97 t (J = 7.5 Hz, 2H);
6.74 d (J = 2 Hz, 1H); 6.95 dd (J = 8, 2 Hz, 1H); 7.01 dd (J = 5,
1 Hz, 1H) ; 7.29 dd (J = 3, 1 Hz, 1H) ; 7.30-7.38 m (4H); 7.47 dd
(J = 5, 3 Hz, 1H) ; 7.58 m (2H) ; 7.73 d (J = 8 Hz, 1H) .
155
Example 180
4-[3-[(1-(4-Methyiphenyl)-2-phenyl-iH-benzimidazol-6-
yl]oxy]phenoxy]butanoic acid methyl ester
a) 6-(3-Methoxyphenoxy)-1-(4-methylphenyl)-2-phenyl-lH-
benzimidazole
was obtained from 6-hydroxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole and 3-methoxybenzeneboronic acid according to
general operating instructions 14.
Flash point 120-122 C
b) 3-[[l-(4-Methyiphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]phenol
was obtained by reaction of 6-(3-methoxyphenoxy)-1-(4-
methylphenyl)-2-phenyl-iH-benzimidazole according to general
operating instructions 6 with the addition of 10 molt of
hexadecyltributyl phosphonium bromide.
Flash point 252-253 C
4-[3-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]phenoxy]butanoic acid methyl ester
was obtained by reaction of 3-[[1-(4-methylphenyl)-2-phenyl-iH-
benzimidazol-6-yl]oxy]phenol with 4-bromobutyric acid methyl
ester according to general operating instructions 8.
1H-NMR (CDC13) 6 = 2.00-2.13 m (2H) ; 2.43 s (3H) ; 2.50 t
(J = 7.5 Hz, 2H); 3.67 s (3H); 3.93 t (J = 7.5 Hz, 2H); 6.44-6.62
m (3H); 6.95 d (J = 2 Hz, 1H); 7.06 dd (J = 8, 2 Hz, 1H); 7.12-
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7.22 m (3H); 7.25-7.39 m (5H); 7.59 m (2H); 7.87 d (J = 8 Hz,
1H) .
Example 181
4-(4-([1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]phenoxy]butanoic acid methyl ester
a) 6-(4-Methoxyphenoxy)-1-(4-methylphenyl)-2-phenyl-iH-
benzimidazole
was obtained from 6-hydroxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole and 4-methoxybenzeneboronic acid according to
general operating instructions 14.
1H-NMR (CDC13): 6 = 2.44 s (3H); 3.79 s (3H); 6.82-6.98 m
(5H); 7.01 dd (J = 8, 2 Hz, 1H); 7.17 d (J = 8 Hz, 2H); 7.25-7.41
m (5H); 7.57 m (2H); 7.82 d (J = 8 Hz, 1H).
b) 4-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl] oxy] phenol
was obtained by reaction of 6-(3-methoxyphenoxy)-1-(4-
methylphenyl)-2-phenyl-lH-benzimidazole- according to general
operating instructions 6 with the addition of 10 mold of
hexadecyltributyl phosphonium bromide.
1H-NMR (D6-DMSO) : 6 = 2.38 s (3H) ; 6.61 d (J = 2 Hz, 1H) ;
6.74 d (J = 8 Hz, 2H); 6.86 d (J = 8 Hz, 2H); 6.91-7.01 m (2H);
7.22-7.41 m (6H); 7.49 m (2H); 7.75 d (J = 8 Hz, 1H); 9.32 s
(1H) .
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4-[4-[(1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]phenoxy]butanoic acid methyl ester
was obtained by reaction of 4-[[1-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]phenol with 4-bromobutyric acid methyl
ester according to general operating instructions 8.
1H-NMR (CDC13) : 6 = 2.03-2.16 m (2H) ; 2.42 s (3H) ; 2.53 t
(J = 7.5 Hz, 2H); 3.69 s (3H); 3.97 t (J = 7.5 Hz, 2H); 6.78-6.94
m (5H); 6.99 dd (J = 8, 2 Hz, 1H); 7.16 d (J = 8, Hz, 2H); 7.24-
7.38 m (5H); 7.57 m (2H); 7.79 d (J = 8 Hz, 1H).
Example 182
[4-[[1-(4-Methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]phenoxy]acetic acid methyl ester
was obtained by reaction of 4-[[1-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]phenol with bromoacetic acid methyl ester
according to general operating instructions 8.
1H-NMR (CDC13) : 6 = 2.43 s (3H) ; 3.82 s (3H) ; 4.61 s (2H) ;
6.78-6.96 m (5H); 7.00 dd (J = 8, 2 Hz, 1H); 7.14 d (J = 8, Hz,
2H); 7.23-7.38 m (5H); 7.56 m (2H); 7.80 d (J = 8 Hz, 1H).
Example 183
4-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]butanoic acid methyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-1H-
benzimidazole with 4-bromobutanoic acid methyl ester according to
general operating instructions 8.
Flash point 107-110 C
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Example 184
6-[[2-Phenyl-l-(3-pyridyl)-1H-benzimidazol-5-yl]oxy]hexanoic acid
methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with pyridine-3-boronic acid
according to general operating instructions 14.
MS (EI): 415 (molecular ion peak)
Example 185
6-[[2-Phenyl-l-(3-pyridyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with pyridine-3-boronic acid
according to general operating instructions 14.
MS (EI) : 415 (molecular ion peak)
Example 186
6-[[2-Phenyl-l-(2-pyridyl)-1H-benzimidazol-5-yl]oxy]hexanoic acid
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with 2-fluoro-pyridine
according to general operating instructions 15.
MS (EI): 401 (molecular ion peak)
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Example 187
6-[[2-Phenyl-l-(2-pyridyl)-1H-benzimidazol.-6-yl]oxy]hexanoic acid
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with 2-fluoro-pyridine
according to general operating instructions 15.
MS (EI): 401 (molecular ion peak)
Example 188
6-[[2-Phenyl-l-(4-pyridyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester
was obtained by reaction of 6-[[2-phenyl]-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester with pyridine-4-boronic acid
according to general operating instructions 14.
MS (EI): 415 (molecular ion peak)
Example 189
6-[[2-(4-Fluorophenyl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-[[4-amino-3-
(phenylamino)phenyl]oxy]hexanoic acid methyl ester with 4-
fluorobenzoyl chloride according to general operating
instructions 5.
MS (EI): 432 (molecular ion peak)
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Example 190
6-[[2-(4-Methoxyphenyl)-1-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-
(phenylamino)phenyl]oxy]hexanoic acid methyl ester with 4-
methoxybenzoyl chloride according to general operating
instructions 5.
MS (EI) : 444 (molecular ion peak).
Example 191
6-[[2-(3-Fluorophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-[[4-amino-3-
(phenylamino)phenyl]oxy]hexanoic acid methyl ester with 3-
fluorobenzoyl chloride according to general operating
instructions 5.
MS (EI): 432 (molecular ion peak)
Example 192
6-[[2-(4-Bromophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was obtained by reaction of 6-[[4-amino-3-
(phenylamino)phenyl]oxy]hexanoic acid methyl ester with 4-
bromobenzoyl chloride according to general operating instructions
5.
MS (EI): 492/494 (molecular ion peaks)
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Example 193
6- [ [2- [4- (Trifluoromethyl)phenyl] -1-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-(phenylamino)phenyl]-
oxy]hexanoic acid methyl ester with 4-(trifluoromethyl)benzoyl
chloride according to general operating instructions 5.
MS (EI): 482 (molecular ion peak)
Example 194
6-[[2-(4-Fluorophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was obtained by reaction of 6-[[2-(4-fluorophenyl)-1-phenyl-lH-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester according to
general operating instructions 9.
MS (EI) : 418 (molecular ion peak-)
Example 195
6-[[1-Phenyl-2-(benzothien-2-yl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-
(phenylamino)phenyl]oxy]hexanoic acid methyl ester with
benzothiophene-2-carboxylic acid chloride according to general
operating instructions S.
Flash point 129-130 C
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162
Example 196
6-[[1-Phenyl-2-(benzothien-2-yl)-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was produced according to general operating instructions 9.
Flash point 340 C (decomposition)
Example 197
6-[[5-Hydroxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
Example 198
6-[[6-Hydroxy-l-(4-methylphenyl)-2-phenyl-iH-benzimidazol-5-
yl]oxy]hexanoic acid isopropyl ester
4,5-Dimethoxy-1,2-dinitrobenzene was hydrogenated to the
diamino compound according to general operating instructions 1,
and said compound was cyclized with trimethyl orthobenzoate to
5,6-dimethoxy-2-phenyl-1H-benzimidazole (flash point 131-133 C)
as crude product according to general operating instructions 3.
This benzimidazole derivative was reacted with 4-
methylphenylboronic acid to form 5,6-dimethoxy-l-(4-
methylphenyl)-2-phenyl-1H-benzimidazole (flash point 145-148 C)
according to general operating instructions 14. After ether
cleavage with hydrobromic acid according to general operating
instructions 6 to 5,6-dihydroxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazole ('H-NMR of hydrobromide (D6-DMSO) : 6 = 2.42 ppm s
(3H); 6.68 s (1H); 7.22 s (1H); 7.40-7.62 m (10H)), it was
alkylated with 6-bromohexanoic acid isopropyl ester according to
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general operating instructions 8. 6-[[5-Hydroxy-l-(4-
methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
isopropyl ester
flash point 137-139 C
and 6-[[6-hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-
yl]oxy]hexanoic acid isopropyl ester
flash point 177-178 C
were obtained.
Example 199
6-[[5-Hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl] oxy] hexanoic acid
was produced according to general operating instructions 9.
Flash point 245-248 C
Example 200
6-[[6-Hydroxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-5-
yl] oxy] hexanoic acid
was produced according to general operating instructions 9.
Flash point 182-184 C
Example 201
6-[(5-Methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester
6-[[5-Hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid isopropyl ester was methylated with methyl
iodide according to general operating instructions 8.
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Flash point 89-91 C
Example 202
6-[[5-Methoxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-6-
yl] oxy] hexanoic acid
was produced according to general operating instructions 9.
Flash point 184-186 C
Example 203
6-([5-Hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
and
Example 204 6-[[6-Hydroxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-5-yl]oxy]-hexanoic acid methyl ester
were produced with 6-bromohexanoic acid methyl ester analogously
to the isopropyl esters by alkylation of 5,6-dihydroxy-l-(4-
methyiphenyl)-2-phenyl-lH-benzimidazole according to general
operating instructions 8. 6-((5-Hydroxy-l-(4-methylphenyl)-2-
phenyl-lH-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was
obtained.
IH-NMR (CDC13): 6 = 1.45-1.58 ppm m (2H) ; 1.65-1.90 m (4H);
2.37 t (J = 7.5 Hz, 2H); 2.48 s (3H); 3.68 s (3H); 3.98 t (J =
7.5 Hz, 2H); 5.68 s (broad) (1H, OH); 6.62 s (1H); 7.18 d (J = 8
Hz, 2H); 7.22-7.38 m (5H); 7.40 s (1H); 7.53 dd (J = 8, 1 Hz, 2H)
and 6-[(6-hydroxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester.
Flash point 141-143 C
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165
Example 205
6-[[5-Methoxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
40 mg of 6-[[5-methoxy-l-(4-methylphenyl)-2-phenyl-1H-
benzimidazol-6-yl]oxy]hexanoic acid was dissolved in 2 ml of
methanol, mixed with 1 drop of concentrated sulfuric acid, and
the mixture was stirred for 2 hours. It was mixed with saturated
potassium bicarbonate solution, diluted with water, extracted
with ethyl acetate, the extracts were dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue was
crystallized from diisopropyl ether..
Flash point 81-82 C
Example 206 6-[[6-Methoxy-l-(4-methylphenyl)-2-phenyl-lH-
benzimidazol-5-yl]oxy]-hexanoic acid methyl ester
6-[[6-Hydroxy-l-(4-methylphenyl)-2-phenyl-lH-benzimidazol-5-
yl]oxy]hexanoic acid methyl ester was methylated with methyl
iodide according to general operating instructions 8.
Flash point 108-110 C
Example 207 .
6-[[6-Methoxy-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-
yl] oxy] hexanoic acid
was produced according to general operating instructions 9.
Flash point 182-184 C
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166
Example 208 6-[(5-Amino-l-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl)oxy]-hexanoic acid methyl ester
a) 3-[(3,4-Dimethylphenyl)amino]-4,6-dinitrophenol
6.6 g of 3,4-dimethylaniline was added to a suspension that
consists of 4 g of 4,6-dinitro-3-fluorophenol (J. Org. Chem.
1991, 5958) in 100 ml of ethanol, and it was stirred for 7 days
at 40 C. After cooling, it was suctioned off, and the residue
was recrystallized from ethanol.
1H-NMR (CDC13): 6 = 2.20 ppm s (6H); 6.43 s (1H); 6.90-7.0
m (2H); 7.14 d (J = 8 Hz, 1H); 9.08 s (1H), 9.70 s (broad) (1H);
10.2-10.6 (1H)
b) 6-[[3-[(3,4-Dimethylphenyl) amino]-4,6-
dinitrophenyl]oxy]hexanoic acid methyl ester
g of 3-[(3,4-dimethylphenyl)amino]-4,6-dinitrophenol was
0-alkylated with 6-bromohexanoic acid methyl ester at 70 C
analogously to general operating instructions 8.
1H-NMR (CDC13): 6 = 1.45-1.88 ppm m (6H); 2.30 s (6H); 2.33
t (J = 7.5 Hz, 2H); 3.68 s (3H);. 3.88 t (J = 7.5 Hz, 2H); 6.45 s
(1H); 7.00-7.08 m (2H); 7.25 d (J = 8 Hz, 1H); 9.03 s (1H); 9.89
s (broad) (1H)
c) 6-[(5-Amino-l-(3,4-dimethyiphenyl)-2-phenyl-lH-benzimidazol-
6-yl)oxy]hexanoic acid methyl ester
2.45 g of 6- [ [3- [ (3, 4-dimethylphenyl) amino] -4, 6-
dinitrophenyl]oxy]hexanoic acid methyl ester was hydrogenated in
methanol according to general operating instructions 1. 500 mg
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167
of the crude product was reacted with benzimidate hydrochloride
according to general operating instructions 4. Contrary to
general operating instructions 4, after being taken up in
solvent, the crude product was not washed with aqueous
hydrochloric acid.
1H-NMR (CDC13): 6 = 1.48-1.58 ppm m (2H); 1.62-1.78 m (2H);
1.78-1.90 m (2H); 2.30 s (3H); 2.38 s (3H); 2.38 t (J = 7.5 Hz,
2H); 3.67 s (3H); 3.93 t (J = 7.5 Hz, 2H); 6.56 s (1H); 6.98-7.08
m (2H); 7.18 s (1H); 7.20-7.32 m (4H); 7.52 dd (J = 8 Hz and 2
Hz, 2H)
Example 209
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (3, 4-dimethylphenyl) -2-
phenyl-lH-benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6-[(5-Amino-l-(3,4-dimethylphenyl)-2-.phenyl-lH-benzimidazol-
6-yl)oxy]hexanoic acid methyl ester was reacted with 4-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
Flash point 186-191 C
Example 210
6-[(5-Amino-2-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-
benzimidazol-6-yl)oxy]hexanoic acid methyl ester
was produced analogously to 6-[(5-amino-l-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
MS (EI): 477 (molecular ion peak)
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168
Example 211
6-[(5-Amino-l-(4-methoxyphenyl)-2-(4-methoxyphenyl)-1H-
benzimidazol-6-yl) oxy]-hexanoic acid methyl ester
was produced analogously to 6-[(S-amino-l-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
MS (EI): 489 (molecular ion peak)
Example 212
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -2- (4-fluorophenyl) -1- (4-
methoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl
ester
6-[(5-Amino-2-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-
benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with
4-chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
Flash point 180-182 C
Example 213
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2- (4-
methoxyphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl
ester
6-[(5-Amino-l-(4-methoxyphenyl)-2-(4-methoxyphenyl)-1H-
benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with
4-chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
Flash point 169-171 C
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169
Example 214
4-[(5-Amino-i-(4-methoxyphenyl)-2-phenyl-iH-benzimidazol-6-
yl)oxy]butanoic acid methyl ester
was produced analogously to 6-[(5-amino-i-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
1H-NMR (CDC13) : 6 = 2.17 ppm tt (J = 8 and 8 Hz, 2H) ; 2.52
t (J = 8 Hz, 2H); 3.68 s (3H); 3.90 s (3H); 3.98 t (J = 7.5 Hz,
2H); 6.54 s (1H); 7.0 d (J = 12 Hz, 2H); 7.18-7.35 m (6H); 7.50-
7.58 m (2H)
Example 215
4- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-
phenyl-1H-benzimidazol-6-yl]oxy]butanoic acid methyl ester
4-[(5-Amino-i-(4-methoxyphenyl)-2-phenyl-lH-benzimidazol-6-
yl)oxy]butanoic acid methyl ester was reacted with 4-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
MS (EI): 605 (molecular ion peak)
Example 216
5-[(5-Amino-l-(4-methoxyphenyl)-2-phenyl-iH-benzimidazol-6-
yl)oxy]pentanoic acid methyl ester
was produced analogously to 6-[(5-amino-l-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
'H-NMR (CDC13):= 5 = 1.78-1.89 ppm m (4H) ; 2.32 t (J = 8 Hz,
2H); 3.68 s (3H); 3.88 s (3H); 3.92 t (J = 7.5 Hz, 2H); 6.53 s
(1H); 7.0 d (J = 12 Hz, 2H); 7.18-7.36 m (6H); 7.48-7.58 m (2H)
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Example 217
5- ([5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-
phenyl-1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester
5-[(5-Amino-l-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]pentanoic acid methyl ester was reacted with 4-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
MS (EI): 619 (molecular ion peak)
Example 218
6-[(5-Amino-l-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester
was produced analogously to 6-((5-amino-l-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
Flash point 129-131 C
Example 219
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-
phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6-[(5-Amino-l-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester was reacted with 4-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
Flash point 168-170 C
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Example 220
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-
phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
was produced according to general operating instructions 9.
Flash point 181-182 C
Example 221
6-[(5-Amino-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester
was produced analogously to 6-[(5-amino-l-(3',4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
Flash point 105-107 C
Example 222
6- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1- (4-methylphenyl) -2-
phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester
6-[(5-Amino-l-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester was reacted with 4-
chlorobenzenesulfonic acid chloride according to general
operating instructions 13.
Flash point 189-191 C
Example 223
6-[[5-[[(4-Chlorophenyl) sulfonyl]amino]-1-(4-methylphenyl)-2-
phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
was produced according to general operating instructions 9.
Flash point 102-105 C
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Example 224 5-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]pentanoic acid methyl ester
was produced analogously to 6-[(5-amino-l-(3,4-dimethylphenyl)-2-
phenyl-1H-benzimidazol-6-yl)oxy]-hexanoic acid methyl ester.
1H-NMR (CDC13) : 6 = 1.82-1.95 ppm m (4H) ; 2.39 t (J = 8 Hz,
2H); 3.69 s (3H); 3.92-4.00 m (2H); 6.60 s (1H); 7.26-7.34 m
(6H); 7.43-7.58 m (5H)
Example 225 5- [ [5- [ [ (4-Chlorophenyl) sulfonyl]amino] -1, 2-
diphenyl-1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester
5-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]pentanoic
acid methyl ester was reacted with 4-chlorobenzenesulfonic acid
chloride according to general operating instructions 13.
Flash point 157-161 C
Example 226 5- [ [5- [ [ (4-Chlorophenyl) sulfonyl] amino] -1,2-
diphenyl-1H-benzimidazol-6-yl]oxy]pentanoic acid
was produced according to general operating instructions 9.
Flash point 236-242 C
Example 227 6- [ [5- [ [ (4-Fluorophenyl) sulfonyl] amino] -1- (4-
methoxyphenyl)-2-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester
6-[(5-Amino-l-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester was reacted with 4-
fluorobenzenesulfonic acid chloride according to general
operating instructions 13.
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MS (EI): 617 (molecular ion peak)
Example 228
6- [ [5- [ [ (4- (Trifluoromethyl)phenyl) sulfonyl] amino] -1- (4-
methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester
6-[(5-Amino-l-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester was reacted with 4-
(trifluoromethyl)benzenesulfonic acid chloride according to
general operating,-instructions 13.
MS (EI): 668 (molecular ion peak)
Example 229
6- [ [5- [ [ (4-Trifluorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-
phenyl-1H-benzimidazol-6-yl]oxylhexanoic acid
was produced according to general operating instructions 9.
Flash point 190-192 C
Example 230 6- [ [5- [ [ (4-Chlorophenyl) sulfonyl]methylamino] -1- (4-
methoxyphenyl)-2-phenyl-1H-benzimidazol-6-ylloxy]hexanoic acid
methyl ester
100 mg of 6- [ [5- [ [ (4-chlorophenyl) sulfonyl] amino] -l- (4-
methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid
methyl ester was dissolved in 3 ml of tetrahydrofuran. 10 mg of
sodium hydride was added to it at 0 C, it was allowed to'stir for
30 minutes, then 50 Al of methyl iodide was added in drops, and
it was allowed to stir for another 60 minutes at 0 C. It was
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.1 ,
mixed with saturated ammonium chloride solution, extracted three
times with ethyl acetate, the organic phases were washed with
water, dried on sodium sulfate and concentrated by evaporation in
a vacuum. The residue was chromatographed on silica gel.
Flash point 178-180 C
Example 231
[[(4-Chlorophenyl)sulfonyl](1,2-diphenyi-1H-benzimidazol-5-
yl]amino] acetic acid methyl ester
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-
yl)benzenesulfonamide was suspended in 0.5 ml of N,N-
dimethylformamide, mixed with 8 mg of sodium hydride and stirred
for 30 minutes at 20 C. 50 mg of bromoacetic acid methyl ester
was added, allowed to stir for 15 hours, mixed with water,
extracted three times with ethyl acetate, the extracts were dried
on sodium sulfate, concentrated by evaporation in a vacuum, and
the residue was chromatographed on silica gel.
1H-NMR (CDC13) : 6 = 3.70 ppm s (3H); 4.52 s (2H); 7.20 d (J
8 Hz, 1H); 7.26-7.58 m (14H); 7.70 d (J = 10 Hz, 2H)
Example 232
[[(4-Chlorophenyl)sulfonyl][1,2-diphenyl-1H-benzimidazol-5-
yl] amino] acetic acid
was produced according to general operating instructions 9.
Flash point 248 C
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Example 233
4-[[(4-Chiorophenyl)sulfonyl](1,2-diphenyl-1H-benzimidazol-5-
yl]amino]butanoic acid methyl ester
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-
yl)benzenesulfonamide was suspended in 0.5 ml of N,N-
dimethylformamide, mixed with 6 mg of sodium hydride and stirred
for 30 minutes at 20 C. 56 mg of 4-bromobutyric acid methyl
ester was added, it was allowed to stir for 15 hours, mixed with
water, extracted three times with ethyl acetate, the extracts
were dried on sodium sulfate, concentrated by evaporation in a
vacuum, and the residue was digested with diisopropyl ether.
Flash point 54-58 C
Example 234
4-[[(4-Chlorophenyl)sulfonyl][1,2-diphenyl-1H-benzimidazol-5-
yl] amino] butanoic acid
was produced according to general operating instructions 9.
Flash point 249-254 C
Example 235
5-[[(4-Chlorophenyl)sulfonyl](1,2-diphenyl-1H-benzimidazol-5-
yllaminolpentanoic acid methyl ester
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-
yl)benzenesulfonamide was suspended in 0.5 ml of N,N-
dimethylformamide, mixed with 8 mg of sodium hydride and stirred
for 30 minutes at 20 C. 60 mg of 5-bromopentanoic acid methyl
ester was added, it was allowed to stir for 15 hours, mixed with
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water, extracted three times with ethyl acetate, the extracts
were dried on sodium sulfate, concentrated by evaporation in a
vacuum, and the residue was chromatographed on silica gel.
1H-NMR (CDC13) : S = 1.46-1.54 ppm m (2H) ; 1.62-1.78 m (2H) ;
2.30 t (J = 8 Hz, 2H); 3.62 s (3H); 3.62 t (J = 8 Hz, 2H); 7.12-
7.53 m (17H)
Example 236
5-[[(4-Chlorophenyl)sulfonyl][1,2-diphenyl-1R-benzimidazol-5-
yl]amino]pentanoic acid
was produced according to general operating instructions 9.
Flash point 123-127 C
Example 237
6-[[(4-Chlorophenyl)sulfonyl][1,2-diphenyl-1H-benzimidazol-5-
yllamino]hexanoic acid methyl ester
6-[[1,2-Diphenyl-1H-benzimidazol-5-yl]amino]hexanoic acid
methyl ester was reacted with 4-chlorobenzenesulfonic acid
chloride according to general operating instructions 13.
MS (EI): 588 (molecular ion peak)
Example 238
7-[[(4-Chlorophenyl)sulfonyl][1,2-diphenyl-1H-benzimidazol-5-
yl]amino]heptanoic acid methyl ester
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-
yl)benzenesulfonamide was suspended in 0.5 ml of N,N-
dimethylformamide, mixed with 8 mg of sodium hydride, and stirred
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for 30 minutes at 20 C. 70 mg of 7-bromoheptanoic acid methyl
ester was added, it was allowed to stir for 15 hours, mixed with
water, extracted three times with ethyl acetate, the extracts
were dried on sodium sulfate, concentrated by evaporation in a
vacuum, and the residue was chromatographed on silica gel.
'H-NMR (CDC13) : 6 = 1.26-1.64 ppm m (8H); 2.27 t (J = 8 Hz,
2H); 3.60 t (J = 8 Hz, 2H); 3.68 S (3H); 7.12 dd (J = 10, 2 Hz,
1H); 7.22 d (J = 10 Hz, 1H); 7.30-7.61 m (15H)
Example 239
7-[[(4-Chlorophenyl)sulfonyl](1,2-diphenyl-iH-benzimidazol-5-
yl] amino] heptanoic acid
was produced according to general operating instructions 9.
Flash point 172-178 C
Example 240
N-(1,2-Diphenyl-lH-benzimidazol-5-yl)-4-fluorobenzenesulfonamide
5-Amino-1,2-diphenyl-lH-benzimidazole was reacted with 4-
fluorobenzenesulfonic acid chloride according to general
operating instructions 13.
Flash point 209-214 C
Example 241
6-[[(4-Fluorophenyl)sulfonyl][1,2-diphenyl-iH-benzimidazol-5-
yl]amino]hexanoic acid methyl ester
150 mg of N-(1,2-diphenyl-lH-benzimidazol-5-yl)-4-
fluorobenzenesulfonamide was suspended in 0.5 ml of N,N-
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dimethylformamide, mixed with 12 mg of sodium hydride and stirred
for 30 minutes at 20 C. 98 mg of 6-bromohexanoic acid methyl
ester was added, allowed to stir for 15 hours, mixed with water,
extracted three times with ethyl acetate, the extracts were dried
on sodium sulfate, concentrated by evaporation in a vacuum, and
the residue was chromatographed on silica gel.
Flash point 128-134 C
Example 242
6-[[(4-Fluorophenyl)sulfonyl][1,2-diphenyl-lH-benzimidazol-5-
yl] amino] hexanoic acid
was produced according to general operating instructions 9.
Flash point 200-210 C
Example 243
6- [ [ [4- (Trifluoromethyl)phenyl] sulfonyl] [1,2-diphenyl-lH-
benzimidazol-5-yl]-amino]hexanoic acid methyl ester
150 mg of 4- (trifluoromethyl) -N- (1, 2-diphenyl-1H-
benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of
N,N-dimethylformamide, mixed with 11 mg of sodium hydride and
stirred for 30 minutes at 20 C. 88 mg of 6-bromohexanoic acid
methyl ester was added, it was allowed to stir for 15 hours,
mixed with water, extracted three times with ethyl acetate, the
extracts were dried on sodium sulfate, concentrated by
evaporation in a vacuum, and the residue was digested with
diisopropyl ether.
Flash point 159-161 C
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Example 244
6- [ [ [4- (Trifluoromethyl)phenyl] sulfonyl] [1,2-diphenyl-lH-
benzimidazol-5-yl]-amino]hexanoic acid
was produced according to general operating instructions 9.
Flash point 224-230 C
Example 245
4-Chloro-N-[1-(4-methoxyphenyl)-2-phenyl-lH-benzimidazol-5-
yl] benzenesulfonamide
a) (2,4 -Dinitrophenyl) (4-methoxyphenyl) amine
1.43 g of 4-(2,4-dinitroanilino)phenol, 500 mg of potassium
carbonate and 0.32 ml of methyl iodide were stirred in 5 ml of
N,N-dimethylformamide for 2 days at 20 C. The mixture was poured
onto water, extracted three times with ethyl acetate, the
extracts were dried on sodium sulfate, concentrated by
evaporation in a vacuum, and the residue was chromatographed on
silica gel.
Flash point 117-127 C
b) 5-Amino-l-(4-methoxyphenyl)-2-phenyl-lH-benzimidazole
(2,4-Dinitrophenyl)(4-methoxyphenyl)amine was hydrogenated
according to general operating instructions 1. The crude product
was cyclized with trimethyl orthobenzoate. to the benzimidazole
derivative according to general operating instructions 3.
'H-NMR (CDC13) : 6 = 3.88 ppm s (3H) ; 6.70 dd (J = 12, 2 Hz,
1H); 6.95-7.06 m (4H); 7.18-7.38 m (7H); 7.53-7.65 m (2H)
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c) 4-Chloro-N-[1-(4-methoxyphenyl)-2-phenyl-lH-benzimidazol-5-
yl]benzenesulfonamide
5-Amino-l-(4-methoxyphenyl)-2-phenyl-1H-benzimidazole was
reacted with 4-chlorobenzenesulfonic acid chloride according to
general operating instructions 13.
Flash point 238-24 C
Example 246
6-[[(4-Chlorophenyl)sulfonyl][1-(4-methoxyphenyl)-2-phenyl-lH-
benzimidazol-5-yl]amino]hexanoic acid methyl ester
75 mg of 4-chloro-N-[1-(4-methoxyphenyl)-2-phenyl-lH-
benzimidazol-5-yl]benzenesulfonamide was suspended in 0.5 ml of
N,N-dimethylformamide, mixed with 6 mg of sodium hydride and
stirred for 30 minutes at 20 C. 44 mg of 6-bromohexanoic acid
methyl ester was added, allowed to stir for 15 hours, mixed with
water, extracted three times with ethyl acetate, the extracts
were dried on sodium sulfate, concentrated by evaporation in a
vacuum, and the residue was chromatographed on silica gel.
MS (EI): 617 (molecular ion peak)
Example 247
6-[[(4-Chlorophenyl)sulfonyl][1-(4-methoxyphenyl)-2-phenyl-lH-
benzimidazol-5-yl]amino]hexanoic acid
was produced according to general operating instructions 9.
Flash point 205-208 C
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Example 248
2,2-Dimethyl-6-((1,2-Biphenyl-1H-benzimidazol-6-yl)oxy]hexanamide
a) 2,2-Dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanonitrile was obtained by reaction of 1,2-diphenyl-6-
hydroxy-1H-benzimidazole with 6-bromo-1,1-dimethylhexanonitrile
according to general operating instructions 8.
Flash point 115-118 C.
b) 2,2-Dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
500 mg of 2,2-dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanonitrile was refluxed for 2 hours in 5 ml of 80%
sulfuric acid. After cooling, it was carefully added to ice
water, the pH was set at 8 with sodium hydroxide solution, it was
extracted three times with ethyl acetate, the extracts were dried
on sodium sulfate, and it was concentrated by evaporation in a
vacuum. The residue was chromatographed on silica gel.
Flash point 115-118 C
Example 249
8-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]octanoic acid methyl
ester
was obtained by reaction of 1,2-diphenyl-6-hydroxy-lH-
benzimidazole with 8-bromooctanoic acid methyl ester according to
general operating instructions 8.
Flash point 92-95 C
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Example 250
8-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]octanoic acid
was produced according to general operating instructions 9.
Flash point 136-140 C
Example 251
6-[[1-(Indan-5-yl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was produced analogously to 6-[[1-(3,4-dimethylphenyl-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester.
Flash point 81-85 C
Example 252
.6-[[1-(Indan-5-yl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid
was produced according to general operating instructions 9.
Flash point 176-180 C
Example 253
7-[[1-(Indan-5-yl)-2-phenyl-lH-benzimidazol-6-yl]oxy]heptanoic
acid methyl ester
was produced analogously to 6-[[1-(3,4-dimethylphenyl)-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester.
Flash point 92-98 C
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Example 254
7-[[1-(Indan-5-yl)-2-phenyl-1H-benzimidazol-6-yl]oxy]heptanoic
acid
was produced according to general operating instructions 9.
Flash point 175-178 C
Example 255
6-[[1-(3-Fluorophenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was produced analogously to 6-[[1-(3,4-dimethylphenyl)-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester.
Flash point 104-106 C
Example 256
6-[[1-(3-Fluorophenyl)-2-phenyl-iH-benzimidazol-6-yl]oxy]hexanoic
acid
was produced according to general operating instructions 9.
Flash point 149-151 C
Example 257
6-[[2-(4-Nitrophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
a) 6-Methoxy-2-(4-nitrophenyl)-1-phenyl-lH-benzimidazole
200 mg of 4-methoxy-N2-phenyl-o-phenylenediamine was
dissolved in 5 ml of N,N-dimethylformamide, mixed with 346 mg of
EEDQ and 234 mg of 4-nitrobenzoic acid, and the mixture was
stirred for 5 hours at 100 C. After cooling, it was mixed with
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water. The precipitate was suctioned off and purified by column
chromatography, taken up in 6N hydrochloric acid and refluxed for
2 hours. After cooling, it was added in drops to saturated
potassium bicarbonate solution. The precipitate was suctioned
off and dried.
Flash point 189-191 C
b) 6-Hydroxy-2-(4-nitrophenyl)-1-phenyl-lH-benzimidazole
was obtained by reaction according to general operating
instructions 6.
'H-NMR (D6-DMSO): 6 = 6.56 ppm d (J = 2 Hz, 1H); 6.87 dd (J
10, 2 Hz, 1H); 7.46 dd (J = 10, 2 Hz, 2H); 7.53-7.70 m (4H);
7.75 d (J = 10 Hz, 2H); 8.20 d (J = 10 Hz, 2H); 9.55 s (broad)
(1H)
c) 6-([2-(4-Nitrophenyl)-1-phenyl-lH-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction according to general operating
instructions 8.
'H-NMR (CDC13) : 6 = 1.45-1.55 ppm m (2H) ; 1.62-1.84 m (4H) ;
2.33 t (J = 8 Hz, 2H); 3.68 s (3H); 3.95 t (J = 8 Hz, 2H); 6.67 d
(J = 2 Hz, 1H); 7.00 dd (J = 10, 2 Hz, 1H); 7.28-7.38 m (2H);
7.52-7.60 m (3H); 7.71 d (J = 10 Hz, 2H); 7.77 d (J = 10 Hz, 1H);
8.13 d (J = 10 Hz, 2H)
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Example 258
6-[[2-(4-Nitrophenyl)-1-phenyl-lH-benzimidazol-6-yl]oxy]hexanoic
acid
was produced according to general operating instructions 9.
Flash point 181-186 C
Example 259
6-[[1-Phenyl-2-(3-pyridinyl)-3.H-benzimidazol-6-yl]oxy]hexanoic
acid methyl ester
was produced analogously to 6-[[1-phenyl-2-(4-pyridinyl)-1H-
benzimidazol-6-yl]oxy]hexanoic acid methyl ester.
Flash point 159-160 C
Example 260
N-(Cyclopropylmethoxy)-6-[(1,2-diphenyl-lH-benzimidazol-6-
yl) oxy] hexanamide
was produced according to general operating instructions 18.
MS (EI): 469 (molecular ion peak)
Example 261
N-Isobutoxy-6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
was produced according to general operating instructions 18.
MS (EI).: 471 (molecular ion peak)
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Example 262
N-(Phenylmethoxy)-6-[2-phenyl-l-(3,4,5-trimethoxyphenyl)-lH-
benzimidazol-6-yl) oxy]-hexanamide
A solution that consists of 50 mg of 6-[2-phenyl-1-(3,4,5-
trimethoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanoic acid in 1 ml
of tetrahydrofuran was added to a solution that consists of 17 mg
of carbonyl diimidazole in 1 ml of tetrahydrofuran, it was
stirred for 30 minutes at 20 C and refluxed for 30 minutes. At
20 C, 16 mg of O-benzylhydroxylamine hydrochloride was added, and
it was allowed to stir for 20 hours. For working-up, ethyl
acetate was added, extracted with 2N hydrochloric acid and
saturated sodium bicarbonate solution, dried on sodium sulfate
and concentrated by evaporation in a vacuum. The residue was
purified by column chromatography on silica gel.
Flash point 145-148 C
Example 263
N-(Cyclopropylmethoxy)-6-[2-phenyl-l-(3,4,5-trimethoxyphenyl)-1H-
benzimidazol-6-yl)oxy]hexanamide
was produced analogously to N-(phenylme.thoxy)-6-(2-phenyl-l-
(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanamide.
MS (EI): 559 (molecular ion peak)
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Example 264
N-Isobutoxy-6-[2-phenyl-l-(3,4,5-trimethoxyphenyl)-1H-
benzimidazol-6-yl)oxy]hexanamide
was produced analogously to N-(phenylmethoxy)-6-[2-phenyl-l-
(3,4,5-trimethoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanamide.
1H-NMR (CDC13) : 6 = 0.94 ppm d (J = 8 Hz, 6H); 1.48-2.03 m
(7H); 2.05-2.18 m (2H); 3.60-3.72 m (2H); 3.76 s (6H); 3.90-4.00
m (2H); 3.96 s (3H); 6.50 s (2H); 6.72 d (J = 2 Hz, 1H); 6.95 dd
(J = 10, 2 Hz, 1H); 7.28-7.38 m (3H); 7.55-7.62 m (2H); 7.74 d (J
= 10 Hz, 1H); 8.20 s (broad) (1H)
Example 265
N-Isopropyl-6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
was produced according to general operating instructions 17.
Flash point 1.07-112 C
Example 266
N,N-Dimethyl-6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
was produced according to general operating instructions 17.
Flash point 83-88 C
Example 267
6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]-1-pyrrolidin-l-
ylhexan-l-one
was produced according to general operating instructions 17.
Flash point 84-88 C
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Example 268
N-(2-Methoxyethyl)-6-[(1,2-diphenyl-iH-benzimidazol-6-
yl)oxy]hexanamide
was produced according to general operating instructions 17.
Flash point 63-68 C
Example 269
N-(3-Methoxypropyl)-6-[(1,2-diphenyl-lH-benzimidazol-6-
yl) oxy] hexanamide
was produced according to general operating instructions 18.
Flash point 84-91 C
Example 270
N-Isobutyl-6-[(1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
was produced according to general operating instructions 17.
1H-NMR (CDC13): 6 = 0.90 ppm d (J = 8 Hz, 6H); 1.44-1.57 m
(2H); 1.65-1.85 m (5H); 2.20 t (J = 8 Hz, 2H); 3.08 t (J = 8 Hz,
2H); 3.94 t (J = 8Hz,.2H); 6.68 d (J = 2 Hz, 1H); 6.96 dd (J =
10., 2 Hz, 1H); 7.25-7.38 m (5H); 7.45-7.58 m (5H); 7.75 d (J = 10
Hz, 1H)
Example 271
N-[(2,2-Dimethylamino)ethyl]-N-methyl-6-[(1,2-diphenyl-iH-
benzimidazol-6-yl)-oxy]hexanamide
was produced according to general operating instructions 17.
1H-NMR (CDC13) (signal of the main rotamer): 6 = 1.44-1.57
ppm m (2H); 1.64-1.84 m (4H); 2.30 s (6H); 2.34 t (J = 8 Hz, 2H);
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2.47 t (J = 8 Hz, 2H); 3.00 s (3H); 3.50 t (J = 8 Hz, 2H); 3.94 t
(J = 8 Hz, 2H); 6.69 d (J = 2 Hz, 1H); 6.96 dd (J = 10, 2 Hz,
1H); 7.25-7.36 m (5H); 7.45-7.56 m (5H); 7.73 d (J = 10 Hz, 1H)
Example 272
N-(2-Methoxyethyl)-N-methyl-6-[(1,2-diphenyl-iH-benzimidazol-6-
yl) oxy] hexanamide
was produced according to general operating instructions 17.
'H-NMR (CDC13) (signal of the main rotamer): 6 = 1.43-1.58
ppm m (2H); 1.63-1.84 m (4H); 2.33 t (J = 8 Hz, 2H); 3.07 s (3H);
3.32 s (3H); 3.47-3.58 m (4H); 3.95 t (J = 8 Hz, 2H); 6.70 d (J =
2 Hz, 1H); 6.96 dd (J = 10, 2 Hz, 1H); 7.25-7.35 m (5H); 7.45-
7.55 m (5H); 7.75 d (J = 10 Hz, 1H)
Example 273 6-[(1,2-Diphenyl-1H-benzimidazol-6-yl)oxy]-1-
morpholin-1-ylhexan-l-one
was produced according to general operating instructions 17.
1H-NMR (CDC13): 6 = 1.47-1.59 ppm m (2H); 1.63-1.88 m (4H);
2.34 t (J = 8 Hz, 2H); 3.42-3.49 m (2H); 3.57-3.70 m (6H); 3.94 t
(J = 8 Hz, 2H); 6.68 d (J = 2 Hz, 1H); 6.96 dd (J = 10, 2 Hz,
1H); 7.23-7.38 m (5H); 7.45-7.56 m (5H); 7.75 d (J = 10 Hz, 1H)
Example 274
N,N-Di(-2-methoxyethyl)-6-[(1,2-diphenyl-lH-benzimidazol-6-
yl) oxy] hexanamide
was produced according to general operating instructions 18.
Flash point 88-98 C
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Example 275
N-Isopentyl-6-((1,2-diphenyl-lH-benzimidazol-6-yl)oxy]hexanamide
was produced according to general operating instructions 18.
Flash point 127-129 C
Example 276
N-(Pyridin-2-yl)-6-[(1,2-diphenyl-1H-benzimidazol-6-
yl)oxy]hexanamide
was produced according to general operating instructions 18.
Flash point 120-124 C
Example 277
N-(Pyridin-3-yl)-6-[(1,2-diphenyl-lH-benzimidazol-6-
yl)oxy]hexanamide
was produced according to general operating instructions 18.
Flash point 154 C
Example 278
6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]-1-piperidin-1-ylhexan-
1-one
was produced according to general operating instructions 18.
Flash point 93-98 C
Example 279
[6-((1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]-1-
hexanoyl]piperidine-4-carbonamide
was produced according to general operating instructions 17.
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Flash point 177-178 C
Example 280 [[6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]-1-
hexanoyl]methylamino]-acetic acid ethyl ester
was produced according to general operating instructions 17.
1H-NMR (CDC13) (signal of the main rotamer): b = 1.23 ppm t
(J = 8 Hz, 3H); 1.45-1.88 m (6H); 2.40 t (J = 8 Hz, 2H); 3.08 s
(3H); 3.93 t (J = 8 Hz, 2H); 4.12 s (2H); 4.18 q (J = 8 Hz, 2H);
6.70 d (J = 2 Hz, 1H); 6.97 dd (J = 10, 2 Hz, 1H); 7.23-7.35 m
(5H); 7.45-7.58 m (5H); 7.75 d (J = 10 Hz, 1H)
Example 281
4-[[6-[(1,2-Diphenyl-lH-benzimidazol-6-yl)oxy]-1-
hexanoyl]]piperazine-l-carboxylic acid ethyl ester
was produced according to general operating instructions 17.
1H-NMR (CDC13) : 6 = 1.27 ppm t (J = 8 Hz, 3H) ; 1.45-1.60 m
(2H); 1.63-1.88 m (4H); 2.36 t (J = 8 Hz, 2H); 3.40-3.53 m (6H);
3.56-3.64 m (2H); 3.93 t (J = 8 Hz, 2H); 4.15 q (J = 8 Hz, 2H);
6.69 d (J = 2 Hz, 1H); 6.96 dd (J = 10, 2 Hz, 1H); 7.23-7.38 m
(5H); 7.45-7.56 m (5H); 7.76 d (J = 10 Hz, 1H)
Example 282
N-Isopropyl-6-[[1-(3,4-dimethyiphenyl)-2-phenyl-iH-benzimidazol-
6-yl]oxy]hexanamide
was produced according to general operating instructions 18.
MS (EI): 469 (molecular ion peak)
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Example 283
N,N-Dimethyl-6-([1-(3,4-dimethylphenyl)-2-phenyl-iH-benzimidazol-
6-yl] oxy]-hexanamide
was produced according to general operating instructions 18.
MS (EI): 455 (molecular ion peak)
Example 284
N,N-Diethyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-benzimidazol-
6-yl]oxy]hexanamide
was. produced according to general operating instructions 18.
MS (EI): 483 (molecular ion peak)
Example 285
N-Isobutyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-iH-benzimidazol-6-
yl] oxy] hexanamide
was produced according to general operating instructions 18.
1H-NMR (CDC13) : 6 = 0.90 ppm d (J = 8 Hz, 6H); 1.44-1.55 m
(2H); 1.58-1.83 m (5H); 2.20 t (J = 8 Hz, 2H); 2.30 s (3H); 2.35
s (3H); 3.09 t (J = 8 Hz, 2H); 3.94 t (J = 8 Hz, 2H); 6.63 d (J =
2 Hz, 1H); 6.94 dd (J = 10, 2 Hz, 1H); 7.02 dd (J = 10, 2 Hz,
1H); 7.10 d (J = 2 Hz, 1H); 7.22-7.35 m (4H); 7.56 dd J 8 Hz,
and 2 Hz, 2H); 7.73 d (J = 10 Hz, 1H)
Example 286
N-Cyclopropyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl] oxy]-hexanamide
was produced according to general operating instructions 18.
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MS (EI): 467 (molecular ion peak)
Example 287
N-Cyclobutyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lR-benzimidazol-
6-yl] -oxy] hexanamide
was produced according to general operating instructions 18.
1H-NMR (CDC13): 6 = 1.42-1.55 ppm m (2H) 1.60-1.88 m (8H);
2.15 t (J = 8 Hz, 2H); 2.28-2.40 m (2H); 2.30 s (3H); 2.35 s
(3H); 3.93 t (J = 8 Hz, 2H); 4.40 quintet (J = 8 Hz, 2H); 5.55 s
(broad) (1H) ; 6.63 d (J = 2 Hz, 1H) ; 6.92 dd (J = 10, 2 Hz, 1H) ;
7.03 dd (J = 10 Hz, and 2 Hz, 1H); 7.08 d (J = 2 Hz, 1H); 7.20-
7.36 m (4H); 7.57 dd (J = 8, 2 Hz, 2H); 7.72 d (J = 10 Hz, 1H)
Example 288
N-tert-Butyl-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-benzimidazol-
6 -yl] oxy] hexanamide
was produced according to general operating instructions 18.
1H-NMR (CDC13) : 6 = 1.32 ppm s (9H) ; 1.42-1.55 m (2H) ;
1.62-1.82 m (4H); 2.10 t (J = 8 HZ, 2H); 2.30 s (3H); 2.36 s
(3H);.3.92 t (J = 8 Hz, 2H); 5.23 s (broad) (1H); 6.66 d (J = 2
Hz, 1H); 6.93 dd (J = 10, 2Hz, 1H); 7.02 dd (J = 10 Hz, and 2 Hz,
1H); 7.09 s (broad) (1H); 7.22-7.36 m (4H); 7.56 dd (J = 8, 2 Hz,
2H) ; 7.73 d (J = 10 Hz, 1H)
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Example 289
(R)-6-[[1-(3,4-Dimethyiphenyl)-2-phenyl-iH-benzimidazol-6-
yl]oxy]1-(2-methoxy-methyl)pyrrolidin-1-ylhexan-l-one
was produced according to general operating instructions 18.
MS (EI): 467 (molecular ion peak)
Example 290
N-(3-Imidazol-1-yl-propyl)-6-[[1-(3,4-dimethylphenyl)-2-phenyl-
1H-benzimidazol-6-yl]oxy]hexanamide
was produced according to general operating instructions 18.
'H-NMR (CDC13): 6 = 1.42-1.53 ppm m (2H); 1.62-2.02 m
(6H); 2.17 t (J = 8 Hz, 2H); 2.27 s (3H); 2.34 s (3H); 3.24 q (J
8 Hz, 2H); 3.92 t (J = 8 Hz, 2H); 3.96 t (J = 8 Hz, 2H); 5.68 s
(broad) (1H); 6.63 d (J = 2 Hz, 1H); 6.88-6.95 m (2H); 7.00 dd (J
= 10 Hz, and 2 Hz, 1H); 7.04-7.10 m (2H); 7.20-7.36 m (4H); 7.50
s (broad) (1H); 7.53 dd (J = 8, 2 Hz, 2H); 7.72 d (J = 10 Hz, 1H)
Example 291
N-(2-Pyridin-2-ylethyl)-6-[[1-(3,4-dimethylphenyl)-2-phenyl-lH-
benzimidazol-6-yl]oxy]hexanamide
was produced according to general operating instructions 18.
1H-NMR (CDC13) : 6 = 1.38-1.52 ppm m (2H) ; 1.62-1.82 m (4H) ;
2.15 t (J = 8 Hz, 2H); 2.30 s (3H); 2.35 s (3H); 2.96 t (J = 8
Hz, 2H); 3.66 q (J = 8 Hz, 2H); 3.90 t (J = 8 Hz, 2H); 6.48 s
(broad) (1H); 6.65 d (J = 2 Hz, 1H); 6.92 dd (J = 10, 2 Hz, 1H);
7.00 dd. (J = 10 Hz, and 2 Hz, 1H); 7.06-7.38 m (7H); 7.53-7.62 m
(3H); 7.72 d (J = 10 Hz, 1H); 8.50 d (broad) (J = 6 Hz, 1H)
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Example 292
N,N-Dimethyl-6-[[2-(4-nitrophenyl)-l-phenyl-lH-benzimidazol-6-
yl] oxy] hexanamide
was produced according to general operating instructions 18.
'H-NMR (CDC13) : 6 = 1.46-1.58 ppm m (2H) ; 1.64-1.88 m (4H) ;
2.32 t (J = 8 Hz, 2H); 2.93 s (3H); 3.00 s (3H); 3.96 t (J = 8
Hz, 2H); 6.65 d (J = 2 Hz, 1H); 7.00 dd (J = 10, 2 Hz, 1H); 7.28-
7.36 m (2H); 7.53-7.61 m (3H); 7.70 d (J = 10 HZ, 2H); 7.76 d (J
= 8 Hz, 1H) ; 8.13 d (J = 8 Hz, 2H)
Example 293
N-Isopropyl-6-[[2-(4-nitrophenyl)-1-phenyl-lH-benzimidazol-6-
yl] oxy] hexanamide
was produced according to general operating instructions 18.
Flash point 162-165 C
Example 294
N-Isopentyl-6-[[2-(4-nitrophenyl)-1-phenyl-lH-benzimidazol-6-
yl] oxy] hexanamide
was produced according to general operating instructions 18.
Flash point 148-154 C
Example 295
N-(3-Methoxypropyl)-6-[[2-(4-nitrophenyl)-1-phenyl-lH-
benzimidazol-6-yl]-oxy]hexanamide
was produced according to general operating instructions 18.
Flash point 104-110 C
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Example 296
N-(3-Methoxypropyl)-6-[[1-(indan-5-yl)-2-phenyl-lH-benzimidazol-
6-yl]oxy]hexanamide
was produced according to general operating instructions 18.
1H-NMR (CDC13) : 6 = 1.43-1.56 ppm m (2H) ; 1.62-1.85 m
(6H); 2.10-2.23 m (4H); 2.95 t (J = 10 Hz, 2H); 3.00 t (J = 10
Hz, 2H); 3.32 s (3H); 3.32-3.40 m (2H); 3.48 t (J = 8 Hz, 2H);
3.93 t (J = 8 Hz, 2H); 6.03 s (broad) (1H); 6.67 d (J = 2 Hz,
1H); 6.93 dd (J = 10, 2 Hz, 1H); 7.03 dd (J = 10, 2 Hz, 1H); 7.12
s (broad) (1H); 7.26-7.35 m (4H); 7.55 dd (J = 10 Hz, 2H); 7.72 d
(J 8 Hz, 1H)
Example 297
6-[[1-(4-Methylphenyl)-2-(3-pyridyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 3-
pyridylcarbaldehyde according to general operating instructions
16.
MS (EI): 429 (molecular ion peak)
Example 298
6-[[1-(4-Methylphenyl)-2-(4-pyridyl)-iH-benzimidazol-6-
yl)oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[(4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 4-
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pyridylcarbaldehyde according to general operating instructions
16.
MS (EI): 429 (molecular ion peak)
Example 299
6-[[1-(4-Methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-
ylloxylhexanoic acid methyl ester
was obtained by reaction of 6-[(4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 2-
thienylcarbaldehyde according to general operating instructions
16.
MS (EI): 434 (molecular ion peak)
Example 300
6-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 3-
thienylcarbaldehyde according to general operating instructions
16.
MS (EI): 434 (molecular ion peak)
Example 301
6-[[2-(3-Indolyl)-1-(4-methylphenyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 3-
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indolylcarbaldehyde according to general operating instructions
16.
MS (EI): 467 (molecular ion peak)
Example 302
6-[[1-(4-Methylphenyl)-2-(2-furyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 2-
furylcarbaldehyde according to general operating instructions 16.
MS (EI): 418 (molecular ion peak)
Example 303
6-[[1-(4-Methylphenyl)-2-(3-furyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 3-
furylcarbaldehyde according to general operating instructions 16.
MS (EI) : 418 (molecular ion peak)
Example 304
6-[[1-(4-Methylphenyl)-2-(5-methyl-2-thienyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 5-
methyl-2-thienyl-carbaldehyde according to general operating
instructions 16.
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MS (EI): 448 (molecular ion peak)
Example 305
6-[[1-(4-Methylphenyl)-2-(4-bromo-2-thienyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 4-
bromo-2-thienylcarbaldehyde according.to general operating
instructions 16.
MS (EI): 512/514 (molecular ion peak)
Example 306
6-([1-(4-Methylphenyl)-2-(3-methyl-2-thienyl)-1H-benzimidazol-6-
yl]oxy]hexanoic acid methyl ester
was obtained by reaction of 6-[[4-amino-3-((4-
methylphenyl)amino)phenyl]-oxy]hexanoic acid methyl ester with 3-
methyl-2-thienylcarbaldehyde according to general operating
instructions 16.
MS (El): 448 (molecular ion peak)
Example 307: Inhibition of Microglia Activation
For in vitro production of AB-activated microglia, primary
rat microglia with synthetic AB-peptide are incubated:
For simulation of AB deposits, synthetic AB peptide is dried
on 96-hole tissue culture plates. A peptide stock solution is
diluted by 2 mg/ml of H2O 1:50 in H20. To coat the 96-hole
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plates, 30 Al of this dilute peptide solution/hole is used, and
it is dried overnight at room temperature.
Primary rat microglia are harvested by mixed glia cultures,
which were obtained from P3 rat brains. In the production of
mixed glia cultures, the brains are taken from 3-day-old rats,
and meninges are removed. The isolation of cells is achieved by
trypsinization (0.25% trypsin solution, 15 minutes at 37 C)).
After undigested tissue fragments are separated with the aid of a
40 m nylon mesh, the isolated cells are centrifuged off (800
rpm/10 min). The cell pellet is resuspended in the culture
medium and moved into 100 ml tissue culture flasks (1
brain/tissue culture flask). The cultivation of the cells is
carried out over a period of 5-7 days in Dulbeccos Modified Eagle
Medium (DMEM, with glutamine), supplemented with penicillin (50
U/mi), streptomycin (40 g/ml) and 10% (v/v) fetal calf serum
(FCS) at 37 C and 5% CO2. During this incubation, an adhesive
cellular film is formed, which mainly consists of astrocytes.
Microglia proliferate as non-adhesive or weakly adhesive cells on
the latter and are harvested via shaking incubation (420 rpm, 1
hour).
To activate the microglia by AE-peptide, 2.5 x 104
microglia/hole are grown on the Ai-coated tissue culture plates
and incubated over a period of 7 days in DMEM (with glutamine),
supplemented with penicillin (50 U/ml), streptomycin (40 g/ml)
and 10% (v/v) fetal calf serum (FCS) at 37 C and 5% CO2. On day
5, a compound according to the invention is added at various
concentrations (0.1, 0.3, 1.3 and 10 M).
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To quantify the microglia reactivity, the metabolic activity
is measured on cultivation day 7 via the reduction of MTS (3-
(4,5-dimethylthiazol-2-yl)-5-(3carboxymethoxyphenyl)-2-
(sulfophenyl)-2H-tetrazolium), Owen's reagent, Baltrop, J. A. et
al. Bioorg. & Med. Chem. Lett 1, 6111 (1991)). The percentage of
inhibition relates to a control that is treated only with DMSO.
The compounds according to the invention inhibit the microglia
activation.
Example 308: Cerebral Brain Infarction in Rats (MCAO Model)
The compounds according to the invention were tested for in
vivo activity in an animal model for cerebral ischemia (stroke),
the MCAO (permanent middle cerebral artery occlusion) model.
One-sided obstruction of the middle cerebral artery (MCA)
triggers a brain infarction, which is caused by the fact that the
corresponding area of the brain is undernourished with oxygen and
nutrients. The result of this undernourishment is a pronounced
cellular degeneration and, subsequently, a strong microglia
activation. This microglia activation reaches its maximum only
after several days, however, and can last for several weeks. To
test the substances, the compounds according to the invention
were administered intraperitoneally 1-6 days after occlusion. On
day 7, the animals were perfused and sacrificed. The extent of
the microglia activation was measured by a modified
immunohistochemical method. Vibratom sections of fixed brains
were incubated with antibodies, whereby said sections detect the
CR3 complement receptor or the MHCII complex on activated
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microglia. The quantification of the primary antibody bond was
carried out by an enzyme-coupled detection system. The treatment
with the compounds according to the invention resulted in a
significant reduction of microglia activation in the brain
hemisphere affected by the brain infarction. The reduction was
at least 20%.
Example 309: Activation of Macrophages
To test substances on macrophages/monocytes, LPS-activated
THP-1 cells were used. For this purpose, 2.5.x 106 cells/ml in
RPMI medium (RPMI 1640 + 10% FCS) were grown. The compounds
according to the invention were added at a concentration of 5 M
and pre-incubated for 30 minutes. The stimulation of the cells
was carried out overnight at 37C with 1 g/ml of LPS. Then, the
medium was harvested, and the amount of TNFa was determined
quantitatively. The treatment of the cells with the substances
according to the invention resulted in a reduction of the amount
of TNFa of at least 30%.
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