Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- 1 - 2~2~~3~
Imidazole derivatives, their method of preparation and
their application in therapeutics
05 The present invention relates to imidazole
derivatives, to their method of preparation and to
their application in therapeutics as agents useful in
the treatment of hypertension, circulatory disorders
and glaucoma.
A number of imidazole derivatives are already
known which are angiotensin II inhibitors useful as
antihypertensives. `
Patent applications EP-A-403 158 and EP-A-
403 159 describe imidazolylalkenoic acids carrying an
unsaturated chain in the 5-position of the imidazole
ring. Patent application EP-A-465 368 describes
, sulfur-containing imidazole derivatives. Patent appli-
cation WO-A-91/00277 describes substituted imidazoles
carrying an aldehyde group in the 5-position of the
` 20 imidazole ring. Patent application EP-A-427 463 des-
cribes substituted N-(imidazolyl)alkylalanine deri-
vatives carrying an amino acid in the 5-position of the
imidazole ring. Patent application EP-A-324 377 des-
cribes imidazole derivatives which are recommended as
diuretics, antiinflammatories and antihypertensives.
Patent application EP-A-253 310 describes imidazole
derivatives carrying a hydroxymethyl substituent in the
5-position of the imidazole ring.
None of these documents of the prior art des-
;~ 30 cribes or suggests imidazole derivatives carrying a
phenylaminomethyl substituent in the 5-position of the
, imidazole ring.
-~ The present invention therefore proposes imi-
dazole derivatives carrying a phenylaminomethyl substi-
; 35 tuent in the 5-position of the imidazole ring.
. . ,: ~: ,.. ,, .: ,, , ::: , :
2 ~ 3 2
-- 2
The compounds according to the invention are
selected from the group consisting of:
(i) the phenylaminomethylimidazoles of the formula
N~ 2 Rl3 3 Rl
R7$~ ( I )
~\ J 6
10 1
R6 ~ ~/ ~ Rs
in which:
- Rl is a C1-C4-alkyl group;
- R2 is the hydrogen atom, a halogen, a Cl-C4-alkylthio
group or a C1-C3-perfluoroalkyl group;
- R3 is the hydrogen atom, a Cl-C4-alkyl group or a
group COR~, in which R~ is a Cl-C4-alkyl group;
20 - R4 is in the 3-, 4-, 5- or 6-position and is the
hydrogen atom, one or more Cl-C4-alkyl, Cl-C4-alkoxy, ,~
azido or nitro groups or one or more halogens, or forms
a 2-aminonaphthyl group with the aminophenyl group to
which it is bonded;
- R5 is a hydrogen atom or a halogen;
- R~ and R7, which are identical or different, are each
a tetrazol-5-yl group or a group COR9, in which R9 is:
- a hydroxyl group,
- a Cl-Cl~-alkoxy group,
- a cyclopropylmethoxy group,
- a phenoxy group,
- a benzyloxy group,
- a 2-phenylethoxy group,
- a glyceryl group,
- an isopropylideneglyceryl group,
.. : . . : ; : .
- ~ : .. , : .. . ........ . .
. ~ :
. ., . ~ . . ~ . .
- a 2-methoxyethoxy group,
- a 2-oxobutoxy group,
- a 1-methyl-2-oxobutoxy group,
- a 2-(N,N-diethylamino)ethoxy group,
05 - a morpholinoethoxy group,
- an N-(ethoxy)nicotinamide group,
- a group O-CHR15-O(CO)-Rl2, in which R15 is
the hydrogen atom or a C1-C3-alkyl group and Rl2 is a
: C1-C7-alkyl group, a cyclopentyl group, a cyclohexyl
. 10 group, a cyclopentylmethyl group or a cyclohexylmethyl
; group,
- an oxyacetate group of the formula O-CHR1~-
CO2-Rl~, in which R1G and R17 are each independently
the hydrogen atom or a C1-C5-alkyl group,
- an oxyacetamide group of the formula O-CH2-
CO-NR1oR11, in which R1o and R11, which are identical
or different, are each a Cl-C4-alkyl group or a hy-
droxyethyl group or form a 4-methylpiperazin-1-yl group
with the nitrogen atom to which they are bonded, or
- an amino group of the formula -NRl8R19, in
which Rl 8 and R19 are each independently the hydrogen
atom, a C1-C~-alkyl group, a methoxy group or a 2-(N,N-
dimethylamino)propyl group, or -NR18R19 is an amino
acid residue of the glycine or valine structure in
which the acid group is optionally protected in the
. form of an ester or amide;
~ RG is also:
, - a group CORI 3 ~ in which R13 is a methylsul-
fonylamino group of the formula -NH-SO2-CH3 or an aryl-
sulfonylamino group of the formula
~=\~ R,4
--NH- SO2~>
.,.. .. :.,
c~
in which Rl4 is the hydrogen atom, a halogen, an azido
group, a C1-C4-alkyl group or a methoxy group and can
be located in the ortho-, meta- or para-position; and
- R3 and R7 taken together can form, with the nitrogen
05 atom and the phenyl group to which they are respecti-
vely bonded, a 2-carboxyindol-1-yl or 2-ethoxycarbonyl-
indol-1-yl ortho-fused nitrogen-containing heterocycle;
and
(ii) the addition salts of the compounds of formula I
with mineral and organic acids or with mineral and
organic bases.
; Cl-C7-Alkyl group is understood here as meaning
a linear, branched or cyclic alkyl group containing up
to 7 carbon atoms. The preferred alkyl groups are
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl
and pentyl groups.
C1-Cl6-Alkoxy group is understood here as
meaning a group in which the alkyl radical is linear,
branched or cyclic and contains up to 16 carbon atoms.
The preferred alkoxy groups are methoxy, ethoxy, pent-
oxy and cyclopropylmethoxy groups.
C -C4-Alkylthio group is understood here as
meaning a group in which the alkyl radical is linear or
branched and contains up to 4 carbon atoms. The pre-
ferred alkylthio groups are methylthio and ethylthio
groups.
Halogen is understood here as meaning the
fluorine atom, the chlorine atom, the bromine atom or
the iodine atom.
The preferred C -C3-perfluoroalkyl groups will
be trifluoromethyl and perfluoroethyl groups.
The preferred addition salts with mineral and
organic acids will be~ the addition salts formed with
hydrochloric, hydrobromic, sulfuric, nitric, phos-
phoric, maleic, malic, acetic, glutamic, tartaric,
` : ` ... .: . :
. . :: , . :: . ,
-- 5
lactic, citric, aspartic, oleic, gluconic, ascorbic,
valeric, succinic, ethylsuccinic, fumaric, oxalic,
gallic, pivalic, capric, decanoic, heptanoic, propio-
nic, caproic, stearic, isethionic, ethanedisulfonic,
05 methanesulfonic, naphthalenesulfonic and metasulfo-
benzoic acids.
The preferred addition salts with mineral
or organic bases will be the addition salts formed
with sodium hydroxide, potassium hydroxide, magnesium
hydroxide, calcium hydroxide, manganese hydroxide,
lithium hydroxide, lysine, cysteine, arginine, mono-
ethanolamine, meglumine, betaine, diethylamine and
dicyclohexylamine.
The preferred compounds according to the
invention are the compounds of formula I in which RG
and R7 are a sulfonylaminocarbonyl group or a group
COOH, as well as their salts obtained by reaction with
an organic or mineral base. The compounds of formula I
salified by reaction with an organic or mineral acid
will be particularly preferred.
The compounds of formula I according to the
invention can be prepared by a method wherein:
(a) a compound of the formula
;
R'2
N /
R 1 ~N~ ~ /X (II')
,~J
R'6 ~J\ R~5
in which:
35 ~ R~1 iS a C1-C4-alkyl group;
2~
~ R'2 ls the hydrogen atom, a halogen, a C1-C4-alkyl-
thio group or a Cl-C3-perfluoroalkyl group;
~ R's is a hydrogen atom or a halogen;
- R'~ is a cyano group or a group COR'g, in which R'g is
05 a C1-Clfi-alkoxy group, a benzyloxy group or an iso-
propylideneglyceryl group; and
- X is a halogen, especially the chlorine atom, or a
paratoluenesulfonyl group,
is subjected to nucleophilic substitution by reaction
with a compound of the formula
,~
R ~N ~ 4 (III')
R7 6 5
; in which:
- R'3 is the hydrogen atom or a Cl-C4-alkyl group;
- R'4 is in the 3-, 4-, 5- or 6-position and is the
hydrogen atom, one or more C1-C4-alkyl, Cl-C4-alkoxy,
azido or nitro groups or one or more halogens, or forms
a 2-aminonaphthyl group with the aminophenyl group to
which it is bonded;
-- - R', is a cyano group or a group COR'g, in which R'g
is:
- a C~-Cl~-alkoxy group, a benzyloxy group,
an isopropylideneglyceryl group, a phenoxy group, a
2-phenylethoxy group, a 2-methoxyethoxy group, a 2-oxo-
butoxy group, a l-methyl-2-oxobutoxy group or a 2-(N,N-
diethylamino)ethoxy group,
- a group O-CHRls-O(CO)-Rl2, in which Rl5 is
the hydrogen atom or a C1-C3-alkyl group and R1z is a
C1-C7-alkyl group, a-cyclopentyl group, a cyclohexyl
group, a cyclopentylmethyl group or a cyclohexylmethyl
group,
,
. - , : . : , : -. : .
- . - .:: -;-. .. -. , . . . :
- . : , : ::: ~: ~ ,, ,-,
~ - , : . .
- . . . : . ,: ~. .. . ,: .. :: :. : - . . . .
r ~ ~
- an oxyacetate group of the formula 0-CHR1,-
C02-Rl~, in which R1 G and R1 7 are each independently
the hydrogen atom or a Cl-C5-alkyl group,
- an oxyacetamide group of the formula 0-CH2-
05 C0-NRloRl1, in which Rlo and Rl1, which are identical
or different, are each a C,-C~-alkyl group or a hy-
droxyethyl group, or
- an amino group of the formula -NR1~R19, in
which R18 and Rl9 are each independently the hydrogen
atom, a C1-C4-alkyl group, a methoxy group or a 2-(N,N-
dimethylamino)propyl group, or -NRl8Rlg is an amino
acid residue of the glycine or valine structure in
.which the acid group is optionally protected in the
form of an ester or amide; and
- R'3 and R', taken together can form, with the nitrogen
atom and the phenyl group to which they are respecti-
vely bonded, a 2-carboxyindol-1-yl or 2-ethoxycarbonyl-
indol-1-yl ortho-fused nitrogen-containing heterocycle,
in an anhydrous medium, in the presence or absence of a
polar or non-polar and aprotic solvent, for example
toluene, xylenes, tetrahydrofuran, dimethylformamide,
chlorinated hydrocarbons, ethers, dioxane, N-methyl-
pyrrolidin-2-one, N,N'-dimethylpropyleneurea or di-
methyl sulfoxide, and in the presence or absence of a
.25 strong base, for example triethylamine, 2,6-lutidine,
` sodium or potassium hydride, potassium or lithium
hexamethyldisilylamide or lithium diisopropylamide, at
a rate of 1 mol of compound II' to 1 to 20 mol of
compound III', at a temperature between room tempera-
ture (15-25 C) and about 200 C, for 0.1 to 12 hours, to
give a compound of the formula
.
~. . ... , . . . : . ., - : :
~ 3'~
N ~ l3 ~
05 ~ R'7 6 (I')
11
R' ~R~s
in which R'1, R'2, R'3, R'~, R'5, RIG and R~7 are defined
as indicated above; and
(b) if necessary, the resulting compounds of formula I'
can be subjected to the following treatments:
(i) the compounds of formula I' in which at least one
of the groups R'~; and R~7 is a group COR~9 in which R~9
is a Cl-C1~-alkoxy group are saponified by the methods
known to those skilled in the art, especially in the
presence of a strong base, for example an aqueous
solution of sodium or potassium hydroxide, in dimeth-
oxyethane or an alcohol such as methanol, to give a
compound of formula I in which RG and R7 are a group
: COOH or RG is a group COOH and R7 is a group COR9 in
which R9 is a Cl-C1~-alkoxy group;
(ii) the compounds thus obtained in stage (i) are
esterified by the methods known to those skilled in the
art, especially by reaction with an appropriate alcohol
or by reaction with an appropriate halogenated deriva-
tive, to give a compound of formula I in which R~; and
R7 are a group COR9 in which R9 is as defined for the
groups R~9 indicated above;
-, (iii) methylsulfonamide or an arylsulfonamide of the
' formula
J
q 35
.
9 ~ 2 8 ~ 2
R~4 ~ SO2-NH2
05 in which R14 is the hydrogen atom, a halogen, an azido
group, a Cl-C4-alkyl group or a methoxy group, is
acylated with a monoacid obtained in stage (i) by the
methods known to those skilled in the art, especially
in the presence of a coupling reagent, for example
-~10 l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
:chloride or N,N-dicyclohexylcarbodiimide, to give a
compound of formula I in which RG is a group CORl3 in
which Rl3 is a methylsulfonylamino group of the formula
-NH-SO2-CH3 or an arylsulfonylamino group of the for-
mula
. ~ R14
--NH- SO2~
:,
20
in which Rl4 is defined as indicated above, R, is a
`group COR9 in which R9 is a Cl-ClG-alkoxy group, and
~R1~ R2, R3, R4 and R5 are defined as indicated above
:for R 1~ R 2~ R'3, R'4 and Rl5 respectively;
(iv) the compounds of formula I' in which R'3 is the
hydrogen atom and R'l, R'2, R~4, R~5, R'~ and Rl7 are
defined as indicated above are acylqted by the methods
known to those skilled in the art, especially by reac-
`tion with an acid anhydride, for example acetic anhy-
-30 dride, to give a compound of formula I in which R3 is a
group CORn in which R8 is a Cl-C4 alkyl group, and Rl,
`R2, R4, Rs~ RG and R7 are defined as indicated above
for R 1~ R 2 ~ R 4, R'5, R'~ and R'7 reSPeCtiVe1Y;
.(v) if necessary, the compounds of formula I' in which
.~35 at least one of the groups RIG and R~7 is a group COR'g
:~`
- - . ~ . . .- . . .
- lo 2~w~
in which R'g is a Cl-C4-alkoxy group, a benzyloxy group
or an isopropylideneglyceryl group are deprotected by
the methods known to those skilled in the art, espe-
cially by treatment in an acid medium or by catalytic
05 hydrogenation, to give a compound of formula I in which
at least one of the groups R~j or R, is a group COOH or
CO-glyceryl and the other group is a group CORg in
which Rg is defined as indicated above for R'g; and
(vi) the compounds of formula I' in which R'~ or R'7 is
a cyano group are converted to a compound of formula I
in which RG or R, is a tetrazol-5-yl group by the
methods known to those skilled in the art, especially
by the 1,3-dipolar cycloaddition of trialkyltin or tri-
aryltin azides.
To obtain the compounds of formula II', it is
recommended to reduce an aldehyde of the formula
N ~ R~2
~ ~ H
~ N ~ (IV)
'~
R' ~ R~s
in which R'1, R'2, R'5 and R'~ are defined as indicated
above, by the methods known to those skilled in the
. art, especially by reaction with NaBH4 or KBH4 in an
0 alcohol, to give an alcohol of the formula
. ~
~, . .
.
~` 35
:;
,: .
~: . - . :. :: : . .
. ~
2 ~ ~
- 11 -
R2
N ~
Il \\
Rl - N ~
05 ¦ OH (V)
,~
R'6 R's
10 in which R'l, R'Z, R'5 and R~G are defined as indicated
above, and then to convert the resulting alcohol to a
derivative of formula II', especially a chlorinated
derivative, by the methods known to those skilled in
the art, especially by reaction with thionyl chloride
in an inert solvent such as a halogenated solvent.
The i~termediates of formula IV in which:
(i) R'l is an n-propyl group, R'2 is a hydrogen atom or
a halogen, R'5 is the hydrogen atom and RIG is a cyano
group or a group COR'g in which Rl9 is a C1-C1G-alkoxy
group or a benzyloxy group, or
(ii) R'l is an n-butyl group, R'2 and R'5 are the
hydrogen atom and RIG is a group COR'g in which R~9 is a
t-butoxy or benzyloxy group,
are novel compounds and form one of the subjects of the
invention.
;l~The intermediates of formula V in which R~1 is
a C1-C4-alkyl group, R'2 is the hydrogen atom or a
halogen, R~5 is the hydrogen atom and R~G is a group
COR'g in which R~9 is a Cl-ClG-alkoxy group or a
; 30 benzyloxy group are novel compounds and form one of the
subjects of the invention.
The intermediates of formula II' in which R'l is
an n-butyl group, R'2 and R~5 are the hydrogen atom and
R~G is a group COR~9 in which R~9 is a t-butoxy or
benzyloxy group are novel compounds and form one of the
, ~
:~:
:`~
1` ~ -, , ~ - , ; . , .. . ; ., ; .;
, . : : . ,, . .~ ~ . . .. .
: . ~ ~, ,,, . - ,,
- 12 ~ 3
subjects of the invention.
The invention will be understood more clearly
from the description of the following Preparatory
Examples, in which the Preparations refer to the inter-
05 mediates and the Examples refer to the products accor-
ding to the invention. These Examples are intended to
illustrate the invention without limiting its scope.
PREPARATION 1
2-Butyl-4-iodo-lH-imidazole-5-carboxaldehyde
A solution of 70.5 g (128.5 10-3 mol) of ammo-
niacal cerium nitrate in 58 ml of water is added drop-
wise to a suspension, at 15C, of 16 g (57-10-3 mol) of
15 2-butyl-4-iodo-lH-imidazole-5-methanol in 48 ml of
acetic acid. The reaction mixture is stirred at room
temperature for 24 hours. A 10 N solution of sodium
hydroxide is then added until the pH is 6. The preci-
pitate formed is extracted with ethyl acetate, washed
with water and then dried over magnesium sulfate to
give 14.7 g (yield: 93%) of a beige solid.
-~ M.p. = 90 C
! PREPARATION 2
Methyl 4-r~4-chloro-5-formyl-2-propyl-lH-imidazol-l-
vl~methyllbenzoate
17.4 g (126 10-3 mol) of potassium carbonate
are added to a solution of 18.15 g (105 10-3 mol) of
4-chloro-2-propyl-lH-imidazole-5-carboxaldehyde and
28.9 g (126 10-3 mol) of methyl 4-bromomethylbenzoate
~y in 275 ml of dimethylformamide. The reaction mixture
is heated at 40 C for 2 hours, with stirring, and then
cooled, poured into water and extracted with ethyl ace-
tate. The organic phases are washed with water until
~ù
'``
:
~,
:.
,. : . : : , . ~. , :.
. . .:: :. - : ~ :: . : : ~
- . : . : . . .... : : :.
:,-: - : -
- 13 - 2~
the washings are neutral, dried over magnesium sulfate
and concentrated. The crude solid obtained is recrys-
tallized from ethanol to give 28 g (yield: 83%) of a
white solid.
05 M.p. = 89 C
The products of Preparations 9, 10, 11 and 31
are obtained by an analogous procedure.
PREPARATION 3
Methyl 4-[(5-formyl-2-propyl-1H-imidazol-l-yl)methyll-
benzoate
7.1 g (72 10-3 mol) of potassium acetate and
then, under nitrogen, 3.48 g of 5% palladium-on-char-
coal are added to a solution of 23.2 g (72-10-3 mol) of
methyl 4-[(4-chloro-5-formyl-2-propyl-lH-imidazol-1-
yl)methyl]benzoate in 230 ml of methanol. The suspen-
sion obtained is stirred under a hydrogen atmosphere at
room temperature for 3 days. The catalyst is filtered
off, the methanol is evaporated off, the residue is
taken up in ethyl acetate and the resulting solution is
washed with water until the washings are neutral.
After drying over magnesium sulfate, the solution is
concentrated and the oily crude product obtained is
chromatographed on silica using a cyclohexane/acetone
mixture (7/3; v/v) as the eluent. Evaporation of the
eluent gives 19 g (yield: 91.6%) of a white solid.
M.p. = 72 C
The following products were obtained by an
analogous procedure:
1.l-Dimethylethyl 4-[(2-butyl-5-formyl-lH-imidazol-l-
vl~methyl~benzoate (Preparation 12)
H NMR (300 MHz; CDCl3; ppm)
0.89 (t, 3H); 1.31 (m, 2H); 1.57 (s, 9H); 1.69 (m, 2H);
2.66 (t, 2H); 5.82 (s, 2H); 7.03 (d, 2H); 7.81 (s, lH);
' ' . ~ . . ' ~
~ . ,: . . . , -
~2~?
- 14 -
7.93 (d, 2H); 9.66 (s, lH).
Ethyl 4-[(2-butyl-5-formyl-lH-imidazol-l-yl!methyll-
benzoate ~Preparation 32)
lH NMR (300 MHz; CDC]3; ppm)
05 0.89 (t, 3H); 1.23 - 1.40 (m, 5H); 1.63 - 1.74 (m, 2H);
2.64 (t, 2H); 4.35 (q, 2H); 5.60 (s, 2H); 7.04 (d, 2H);
7.82 (s, lH); 7.97 (d, 2H); 9.67 (s, lH).
PREPARATION 4
Methyl 4-r(2-butyl-5-formyl-4-trifluoromethyl-lH-
; imidazol-1-yl)methyllbenzoate
A solution of 32 ml of dibromodifluoromethane
in 32 ml of dimethylformamide is added in 2 hours to a
15 suspension of 82 g of cadmium powder in 183 ml of
dimethylformamide and room temperature. The reaction
mixture is stirred for 2 hours at room temperature and
then left to stand for 30 minutes. 8.34 g (58-10-3
mol) of cuprous bromide and then a solution of 7.08 g
20 (16.6-10-3 mol) of methyl 4-[(2-butyl-5-formyl-4-iodo-
lH-imidazol-l-yl)methyl]benzoate in 50 ml of dimethyl-
;l formamide are added to a mixture of 70 ml of the above
solution in 75 ml of hexamethylphosphorotriamide at
0 C. The reaction mixture is heated at 70 C for 4
hours. After the mixture has cooled, 600 ml of water
; are added and extraction is carried out with ethyl
acetate. The organic phases are washed with water,
dried over magnesium sulfate, filtered and evaporated
under reduced pressure. The resulting oil is purified
; 30 by chromatography on silica using a toluene/ethyl ace-
~ tate mixture (9/1; v/v) as the eluent to give 5.71 g
`~ (yield: 93%) of an ochre solid.
M.p. = 59 C
- 15 ~ 2~9 2 ~5 2
PREPARATION 5
4-~(2-Butyl-5-formyl-lH-imidazol-l-yl)methyllbenzoic
acid
05 25 ml of water and 3 g (75 10-3 mol) of sodium
hydroxide are added to a solution of 16 g (53.3 10-3
mol) of methyl 4-[(2-butyl-5-formyl-lH-imidazol-1-yl)-
methyl]benzoate in 100 ml of methanol. The reaction
mixture is refluxed for 5 hours. The methanol is eva-
-;10 porated off under reduced pressure and 150 ml of water
are added to the residue. The mixture is washed with
twice 50 ml of ethyl acetate. The aqueous phase is
acidified to pH 6 with a 1 N solution of hydrochloric
`~acid and extracted with 2 times 100 ml of an ethyl
;15 acetate/n-butanol mixture (80/20; v/v). The organic
phases are washed with water, dried over magnesium
sulfate, filtered and evaporated under reduced pressure
to give 14 g (yield: 94%) of a yellow solid.
M.p. = 148 C
The product of Preparation 33 is obtained by a
procedure analogous to Preparation 5.
:.:
~ PREPARATION 6
.,
Phenylmethyl 4-[(2-butyl-5-formyl-lH-imidazol-l-yl)-
methyl~benzoate
5 . 4 g ( 50 10-3 mol) of benzyl alcohol, 5.85 g
~48~10-3 mol) of 4-dimethylaminopyridine and 9.17 g
(48-10-3 mol) of 1-(3-dimethylaminopropyl)-3-ethyl-
~;~30 carbodiimide hydrochloride are added to a solution of
13.5 g (47.2-10-3 mol) of 4-[(2-butyl-5-formyl-lH-
imidazol-1-yl)methyl]benzoic acid in a mixture of 5 ml
of dimethylformamide and 200 ml of dichloromethane.
The reaction mixture is stirred at room temperature for
20 hours and then washed with twice 60 ml of water.
;- ,
.
- , , , ~ i ,~ , . ,
.
- 16 -
The organic phase is dried over magnesium sulfate, fil-
tered and evaporated under reduced pressure. The resi-
due is purified ~y chromatography using a hexane/
acetone mixture (70/30; v/v) as the eluent to give 17 g
05 (yield: 95%) of a yellow oil.
1H NMR (300 MHz; CDCl3; ppm)
0.88 (t, 3H); 1.35 (m, 2H); 1.72 (m, 2H); 2.65 (t, 2H);
5.34 (s, 2H); 5.62 (s, 2H); 7.04 (d, 2H); 7.4 (m, 5H);
7.80 (s, lH); 8.03 (d, 2H); 9.66 (s, lH).
The product of Preparation 34 and the following
products are obtained by an anal~gous procedure:
Pentyl 4-r(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-
benzoate ~PreDaration 35)
~` lH NMR (300 MHz; CDCl3; ppm)
`I 15 0.89 (m, 6H); 1.18 - 1.40 (m, 5H); 1.62 - 1.77 (m, 5H);
2.63 (t, 2H); 4.29 (t, 2H); 5.63 (s, 2H); 7.05 (d, 2H);
7.81 (s, lH); 7.97 (d, 2H); 9.67 (s, lH).
Butyl 4-~(2-butyl-5-formyl-lH-imidazol-l-yl ! methyl~-
penzoate (Preparation 36!
' 20 1H NMR (300 MHz; CDCl3; ppm)
1 0.86 (t, 3H); 0.96 (t, 3H); 1.31 - 1.49 (m, 4H); 1.64 -
1.78 (m, 4H); 2.63 (t, 2H); 4.30 (t, 2H); 5.62 (s, 2H);
7.04 (d, 2H); 7.81 (s, lH); 7.97 (d, 2H); 9.67 (s, lH).
2-Methylpropyl 4-[(2-butyl-5-formyl-lH-imidazol-1-yl~-
methyllbenzoate (Preparation 37)
i~ lH NMR (300 MHz; CDCl3; ppm)
0.88 (t, 3H); 0.99 (d, 6H); 1.31 - 1;38 (m, 2H); 1.64 -
1.75 (m, 2H); 2.06 (m, lH); 2.63 (t, 2H); 4.08 (d, 2H);
5.63 (s, 2H); 7.05 (d, 2H); 7.81 (s, lH); 7.98 (d, 2H);
9.67 (s, lH).
Cyclopropylmethyl 4- r ( 2-butyl-5-formyl-lH-imidazol-l-
vl~methyl~benzoate (Preparation 38
~H NMR (300 MHz; CDCl3; ppm)
0.35 (m, 2H); 0.59 (m, 2H); 0.88 (t, 3H); 1.21 - 1.25
(m, lH); 1.29 - 1.40 (m, 2H); 1.60 - 1.75 (m, 2H); 2.63
., : ., . ' : ,, ~: ' : ' ! ' ' '
~.J ~
- 17 -
(t, 2H); 4.12 (d, 2H); 5.63 (s, 2H); 7.05 (d, 2H); 7.81
(s, lH); 7.97 (d, 2H); 9.67 (s, lH).
3-Methylbutyl 4-~(2-butyl-5-formyl-lH-imidazol-l-yl~-
methyllbenzoate (Preparation 39l
05 lH NMR (300 MHz; CDCl3; ppm)
0.88 (t, 3H); 0.97 (d, 6H); 1.23 - 1.41 (m, 3H); 1.61 -
1.82 (m, 4H); 2.63 (t, 2H); 4.35 (t, 2H); 5.63 (s, 2H);
7.05 (d, 2H); 7.81 (s, lH); 7.97 (d, 2H); 9.67 (s, lH).
Phenylmethyl 4-r(2-butyl-4-chloro-5-formyl-lH-imida~ol-
l-yl)methyl~benzoate (Preparation 40l
H NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.29 - 1.37 (m, 2H); 1.61 - 1.72 (m, 2H);
2~60 (t, 2H); 5.35 (s, 2H); 5.59 (s, 2H); 7.07 (d, 2H);
7.34 - 7.44 (m, 5H); 8.02 (d, 2H).
PREPARATION 62
Methyl 4-r[2-butyl-5-formyl-4-methylthio-lH-imidazol-l-
yllmethylJbenzoate
~ 20 3.24 g (4.62-l0-2 mol) of sodium thiomethylate
;~ are added to a solution of 3.87 g (1.15- 10-2 mol) of
methyl 4-[(4-chloro-5-formyl-2-butyl-lH-imidazol-l-yl)-
methyl]benzoate in 40 ml of methanol. The reaction
mixture is refluxed for 4 hours, with stirring, and
then cooled, poured into a 10% aqueous solution of
citric acid at 0 C and extracted with ethyl acetate.
The organic phases are washed with water until the
washings are neutral, dried over magnesium sulfate and
concentrated. The oily residue obtained is chromato-
graphed on silica using a toluene/ethyl acetate mixture
(8/2; v/v) as the eluent. Evaporation of the eluent
gives 2.8 g (yield: 70%) of a yellow solid.
M.p. = 72 - 74 C
,
':; - . , : .
- ~, . , : - - . .
' : ~ . ~ ~ . .. '
.
'2~8~2
- 18 -
PREPARATION 7
ethyl 4- r ( 2-butyl-5-hydroxymethyl-lH-imidazol-1-yl)-
methyllbenzoate
05 5.92 g (19.7-10-3 mol) of methyl 4-[(2-butyl-5-
formyl-lH-imidazol-l-yl)methyl]benzoate are dissolved
in 60 ml of methanol and the solution obtained is
cooled with an ice bath. 895 mg (23.6-10-3 mol) of
sodium borohydride are then added in portions over 30
minutes, with stirring. After 10 minutes, the methanol
is evaporated off and the residue is diluted with water
and extracted with methylene chloride. The combined
organic phases are washed with water, dried over mag-
nesium sulfate and concentrated to give 5.22 g (yield:
88%) of a white solid.
M.p. = 144 C
The products of Preparations 13 to 21 and 41 to
49 and the following product were prepared by an
analogous procedure:
4-r~2-Butyl-5-hydroxymethyl-lH-imidazol-1-yl)methyl~-
benzonitrile (Preparation 50
M~p. = 109 C
.
PREPARATION 8
Methyl 4- r 2-butyl-5-chloromethyl-lH-imidazol-1-yl~-
methyllbenzoate hydrochloride
5.2 g (17.2-10-3 mol) of methyl 4-[~2-butyl-
5-hydroxymethyl-lH-imidazol-1-yl)methyl]benzoate are
dissolved in 50 ml of chloroform and the solution is
cooled with an ice bath. 10.23 g (86-10-3 mol) of
thionyl chloride are then added dropwise, with stir-
ring. Stirring is maintained at this temperature for
15 minutes after the addition has ended. The chloro-
; 35 form is evaporated off and toluene is then added and
~ ,~. ~, ,,. ;. ; , .. .
:` " -:'` ,;,: ': , ,. , '' ,: :. `,
- 1 9 ~ S~ ~ 2 ,~
evaporated off to give 6.1 g (yield: 99.3%) of a beige
solid.
M.p. = 158 C
The products of Preparations 22 to 29, 51 and
05 53 to 59 and the following products were obtained by an
analogous procedure:
Methyl 4- r f2-butyl-5-chloromethyl-4-trifluoro~ethyl-lH-
imidazol-l-yl)methyllbenzoate (Preparation 30)
Yellow oil
- 10 1H NMR (300 MHz; CDCl3; ppm)
~ 0.87 (t, 3H); 1.33 (m, 2H); 1.68 (m, 2H); 2.60 (t, 2H);
- 3.92 (s, 3H); 4.52 (s, 2H); 5.29 (s, 2H); 7.06 (d, 2H);
8.03 (d, 2H).
4- r ( 2-Butyl-5-chloromethyl-lH-imidazol-l-yl)methyll-
benzonitrile hydrochloride (Preparation 60
M.p. = 95 C
Phenylmethvl 4- r ( 2-butvl-4-chloro-5-chloromethyl-lH-
imidazol-l-vl)methyllbenzoate (Preparation 61
lH NMR ~300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.27 - 1.39 (m, 2H); 1.62 - 1.72 (m, 2H);
2.55 (t, 2H); 4.44 (s, 2H); 5.24 (s, 2H); 5.36 (s, 2H);
7.05 (d, 2H); 7.16 - 7.45 (m, 5H); 8.05 (d, 2H).
PREPARATION 63
Pentyl 2-methyl-6-nitrobenzoate
6 ml (0.082 mol) of thionyl chloride are added
to a suspension of 5 g (0.0276 mol) of 2-nitro-6-
methylbenzoic acid in 90 ml of toluene. The reaction
mixture is refluxed for 3.5 h, with stirring, and eva-
porated under reduced pressure. 45 ml of n-pentanol
and then added to the oily residue and the mixture is
refluxed for 2 hours, with stirring. After cooling,
100 ml of water are added, a saturated aqueous solution
of sodium bicarbonate is added until the pH is basic,
~, , ... ::
- 20 - c~g~r~ ~
and the mixture is extracted with toluene. The organic
phases are washed with water, dried over magnesium sul-
fate and concentrated. After distillation of the n-
pentanol under reduced pressure, 6.74 g of a yellow oil
05 are obtained (yield: 97~).
1H NMR (300 MHz; CDCl3; ppm)
0.89 (t, 3H); 1.36 (m, 4H); 1.77 (m, 2H); 2.45 (s, 3H);
4.37 (t, 2H); 7.43 (t, lH); 7.53 (d, lH); 8.00 (d, lH).
,:
PREPARATION 64
,~ .
2-[(2-Aminobenzoyl)oxyl-N~N-dipropylacetamide
15 g (0.084 mol) of N,N-dipropylchloroacet-
amide, 1.26 g (8.44-10-3 mol) of sodium iodide and
11.1 g (0.1 mol) of triethylamine are added to a
solution of 15 g (0.1 mol) of anthranilic acid in 150
ml of dimethylformamide. The mixture is stirred over-
i night at room temperature. A saturated solution of
sodium bicarbonate is added and extraction is carried
out with ethyl acetate. The organic phases are washed
with water until the pH is neutral, dried over mag-
nesium sulfate and concentrated. The oil obtained is
- crystallized by stirring in ether to give 7.86 g
- (yield: 33.4%) of the expected product.
M.p. = 64 C
The following products are obtained by a pro-
cedure analogous to Preparation 64:
2-r(2-Aminobenzoyl~oxylpentan-3-one (Preparation 65)
lH NMR (300 MHz; CDCl3; ppm)
1.09 (t, 3H); 1.49 (d, 3H); 2.58 (m, 2H); 5.28 (q, lH);
5.70 (s, 2H); 6.60 (m, 2H); 7.28 (m, lH); 7.91 (m, lH).
Ethyl 2- r ( 2-aminobenzoyl)oxylacetate (Preparation 66)
lH NMR (300 MHz; CDCl3; ppm)
1.30 (t, 3H); 4.25 (q, 2H); 4.80 (s, 2H); 5.69 (s, 2H);
6.66 (m, 2H); 7.29 (m, lH); 7.93 (m, lH).
- 21 ~ c~3~2~ 2
Pentyl 2-[(2-aminobenzoyl~oxylacetate (Preparation 67)
1H NMR (300 MHz; CDCl3; ppm)
0.88 (m, 3H); 1.28 (m, 4H); 1.63 (m, 2H); 4.16 (t, 2H);
4.80 (s, 2H); 5.68 (s, 2H); 6.65 (m, 2H); 7.28 (m, lH);
05 7.92 (m, lH).
PREPARATION 68
'
Cyclopropylmethyl 2-aminobenzoate
1.77 g (0.044 mol) of sodium hydroxide are
added to a suspension of 9 g (0.0552 mol) of isatoic
anhydride in 14.3 g (0.198 mol) of cyclopropylmethanol.
The reaction mixture is heated at 80 C for 3 hours,
with stirring, and then poured into water and extracted
with ethyl acetate. The organic phases are washed with
water until the pH of the washings is neutral, dried
over magnesium sul~ate and concentrated under reduced
pressure to give 7.51 g (yield: 64%) of an ochre oil.
lH NMR (300 MHz; CDCl 3; ppm)
0.34 (m, 2H); 0.61 (m, 2H); 1.25 (m, lH); 4.10 (d, 2H);
5.70 (s, 2H); 6.65 (m, 2H); 7.25 (m, lH); 7.92 (m, lH).
The product of Preparation 69 and the following
products are obtained by a procedure analogous to Pre-
. paration 68:
1-Methylpentyl 2-aminobenzoate (Preparation 70)
H NMR (300 MHz; CDCl3; ppm)
0.86 (m, 3H); 1.31 - 1.73 (m, 2H); 5.10 (m, lH); 5.71
(s, 2H); 6.61 (m, 2H); 7.25 (m, lH); 7.88 (m, lH).
2- r N.N-Diethylaminolethyl 2-aminobenzoate lPreparation
~11
lH NMR (300 MHz; CDCl3; ppm)
1.06 (t, 6H); 2.63 (q, 4H); 2.83 (t, 2H); 4.36 (t, 2H);
5.70 (s, 2H); 6.63 (m, 2H); 7.25 (s, lH); 7.86 (d, lH).
- 22 - ~ 2
PREPARATION 72
2- r ( 2-Aminobenzoyl ! oxy l-N N-diethylpropionamide
2 g (6.66-10-2 mol) of NaH as an 80~ suspension
05 in oil are added to a solution of 8.31 g t6.06-10-2
mol) of anthranilic acid in 45 ml of 1,3-dimethyl-
3,4,5,6-tetrahydro-(lH)-pyrimidin-2-one (DMPU). The
mixture is stirred at room temperature for 0.5 h and a
solution of 10.91 g (6.66-10-2 mol) of N,N-diethyl-2-
chloropropionamide in 10 ml of DMPU is then added drop-
wise. The reaction mixture is then stirred at 100DC
for 1.5 h. After cooling, a saturated solution of
sodium bicarbonate is added and the precipitate ob-
tained is filtered off. After washing with water and
drying, 14.31 g (yield: 89%) of the expected product
are obtained.
M.p. = 134 C
The products of Preparations 73, 74 and 75 and
the following products are obtained by a procedure
analogous to Preparation 72:
1-[(2-Aminobenzoyl)oxy]ethyl 2-ethylbutanoate (Prepa-
ration 76)
lH NMR (300 MHz; CDCl3; ppm)
0.89 (t, 6H); 1.47 - 1.66 (m, 7H); 2.22 (m, lH); 5.73
(s, 2H); 6.63 (m, 2H); 7.13 (q, lH); 7.26 (m, lH); 7.84
(m, lH).
- r (2-Aminobenzoyl)oxylethyl cyclopehtylcarboxylate
~Preparation 77)
lH NMR (300 MHz; CDCl3; ppm)
1.53 - 1.87 (m, llH); 2.75 (m, lH); 5.73 (s, 2H); 6.61
(t, 2H); 7.10 (q, lH); 7.27 (m, lH); 7.83 (m, lH).
- r (2-Aminobenzoyl)oxylethyl cyclohexylcarboxylate
~Preparation 78)
lH NMR (300 MHz; CDCl~; ppm)
1.18 - 1.88 (m, 13H); 2.31 (m, lH); 5.74 (s, 2H); 6.63
.. . .. .... .. . ..
- : ., . :- :. : :. ,
' , : ' , ,. , , !.' :'-' .
- 23 - ~ ~2~
(m, 2H); 7.09 (m, lH); 7.28 (m, lH); 7.83 (m, lH).
r ~2-Amino~enzoyl)oxy]methyl hexanoate ~Preparation 79)
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.29 (m, 4H); 1.63 (m, 2H); 2.37 (t, 2H);
05 5.7 (s, 2H); 5.96 (s, 2H); 6.63 (m, 2H); 7.29 (m, lH);
7.88 (d, lH).
1-~(2-Aminobenzoyl)oxy]ethyl hexanoate (Preparation 80)
NMR (300 MHz, CDCl3; ppm)
0.26 (t, 3H); 1.30 (m, 4H); 1.60 (m, 5H); 2.35 (t, 2H);
5.76 (s, 2H); 6.63 (m, 2H); 7.11 (m, lH); 7.27 (m, lH);
7.86 (d, lH).
1-~(2-Aminobenzoyl)oxylethyl cyclohexylacetate (Prepa-
ration 81)
lH NMR (300 MHz; CDCl3; ppm)
0.91 - 1.42 (m, 5H); 1.55 - 1.75 (m, 9H); 2.20 (m, 2H);
5.74 (s, 2H); 6.63 (m, 2H); 7.12 (m, lH); 7.27 (m, lH);
7.85 (m, lH).
l-r(2-Aminobenzoyl)oxylethyl cyclopentylacetate (Prepa-
ration 82)
lH NMR (300 MHz; CDCl,; ppm)
; 1.15 (m, 2H); 1.58 (m, 7H); 1.81 (m, 2H); 2.23 (m, lH);
2.35 (m, 2H); 5.73 (s, 2H); 6.61 (d, lH); 7.09 - 7.29
(m, 2H); 7.85 (d, lH).
r r 2-Aminobenzoyl)oxy]methyl 2,2-dimethylpropionate
(Preparation 83
lH NMR (300 MHz; CDCl3; ppm)
1.49 (s, 9H); 4.69 (s, 2H); 5.66 (s, 2H); 6.65 (m, 2H);
7.27 (m, lH); 7.93 (m, lH).
PREPARATION 84
N- r 3-(N,N-Dimethylamino)propyll-2-aminobenzamide
8.16 g (8-10- 2 mol) of N,N-dimethylpropane-
diamine are added slowly to 6.52 g (4 D 10-2 mol) of
isatoic anhydride and the mixture is then heated at
.,- ~ .. ~....... . . -
.. : . . . .. .. . .
- 24 -
80 C for 1 hour. After cooling, 150 ml of water are
added and extraction is carried out with ethyl acetate.
The organic phases are washed with water until the pH
of the washings is neutral, dried over sodium sulfate,
05 filtered and evaporated under reduced pressure to give
7.8 g (yield: 88%) of the expected product.
M.p. = 76 C
PREPARATION 85
N.N-Diethyl-2-rN-(2-aminobenzoyl~aminoJacetamide
3.33 g (2-10-2 mol) of aminoacetic acid di-
ethylamide and 3.03 g (3-10-2 mol) of triethylamine are
added successively to a solution of 3.27 g (2-10-2 mol)
of isatoic anhydride in 20 ml of dimethylformamide.
The reaction mixture is subsequently heated at 70 C for
1 hour and then cooled, water is added and extraction
is carried out with ethyl acetate. The organic phases
are washed with water until the washings are neutral,
dried over magnesium sulfate, filtered and concentrated
under reduced pressure to give 3.34 g (yield: 67%) of
the expected product.
MLp. = 62 C
The following product is obtained by a pro-
cedure analogous to Preparation 85:
Ethyl N-r2-aminobenzoyl~-L-valine (Preparation 86)
H NMR (300 MHz; CDCl3; ppm)
1.0 (t, 6H); 1.31 (t, 3H); 2.26 (m, lH); 4.23 (m, 2H);
4.72 (m, lH); 5.5 (s, 2H); 6.57 (d, lH); 6.69 (m, 2H);
7.23 (t, lH); 7.41 (d, lH).
PREPARATION 87
Pentyl 2-amino-6-methylbenzoate
0.62 g of 10% palladium-on-charcoal is added
.. : .. ~ . . . ..
:~ ::, . .:: .. , -. -: .
- 25 - 2~2~2
under a nitrogen atmosphere to a solution of 6.2 g
(0.0247 mol) of pentyl 2-nitro-6-methylbenzoate in 200
ml of ethanol. The reaction medium is then placed
under a hydrogen atmosphere and stirred for 6 hours.
05 After filtration, the ethanol is evaporated off under
reduced pressure to give 5.22 g (yield: 96%) of an
ochre oil.
lH NMR (300 MHz; CDCl3; ppm)
0.92 (t, 3H); 1.38 (m, 4H); 1.73 (m, 2H); 2.44 (s, 3H);
4.32 (t, 2H); 5.2 (s, 2H); 5.54 (d, 2~); 7.07 (t, lH).
PREPARATION 88
Pentyl 2-amino-6-chlorobenzoate
10.6 g (0.087 mol) of 4-dimethylaminopyridine,
16.6 g (0.087 mol) of 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride and 7.65 g (0.087 mol)
of n-pentanol are added to a suspension of 15 g (0.087
mol) of 2-amino-6-chlorobenzoic acid in 250 ml of
dichloromethane. The reaction mixture is stirred at
room temperature for 20 hours and then washed with 1 x
50 ml of a 10% solution of citric acid followed by 2 x
50 ml of water. The organic phase is dried over mag-
nesium sulfate, filtered and evaporated under reduced
pressure. The residue is purified by flash chromato-
graphy on silica using a cyclohexane/acetone mixture
(90/10; v/v) as the eluent to give 4.64 g (yield: 22%)
~; of a yellow oil.
H NMR (300 MHz; CDC13; ppm)
0.92 (t, 3H); 1.38 (m, 4H); 1.72 (q, 2H); 4.33 (t, 2H);
4.84 (s, 2H); 6.55 (d, lH); 6.73 (d, lH); 7.07 (t, lH).
A number of intermediates have been collated in
Tables A, B, C and D, in which the symbols used are
identical to those in Tables I to VII.
.
.. : . . . . ~ .. , .;, ~ , .:
. :: .. .:: :.. : .:. - .--: : , ,
: ;: . .~ . , .,. :: ,
: ' '.':. ` : . ~ . .
- 26 -
Example 1:
Methyl 2-r r ~2-butyl-1-r (4-(methoxycarbonyl~phenyl~-
methyll-lH-imidazol-5-yl]methyl]aminolbenzoate
05 8 g (22.3-10-3 mol) of methyl 4-[(2-butyl-
5-chloromethyl-lH-imidazol-l-yl)methyl]benzoate hydro-
chloride are suspended in 80 ml of anhydrous toluene.
10.15 g (67 . 1 10-3 mol) of methyl 2-aminobenzoate and
then 4.79 g (44.7 10-3 mol) of 2,6-dimethylpyridine are
added. The reaction mixture is re~luxed for 8 hours
and then poured into iced water. The aqueous phase is
extracted with ethyl acetate. The combined organic
phases are washed with water until the washings are
neutral, dried over magnesium sulfate and concentrated
lS to give 11.8 g of a brown oil, which is purified by
chromatography using a toluene/isopropanol mixture
(9/1; v/v) as the eluent. After evaporation of the
eluates, 9 g (yield: 92.3%) of an orange oil are
obtained.
lH NMR (300 MHz; CDCl3; ppm)
; 0.87 (t, 3H); 1.34 (m, 2H); 1.68 (m, 2H); 2.56 (t, 2H);
3.77 (s, 3H); 3.91 (s, 3H); 4.19 (d, 2H); 5.18 (s, 2H);
6.58 - 6.67 (m, 2H); 6.92 (d, 2H); 7.04 (s, lH); 7.30
(t, lH), i.67 (t, lH); 7.82 (d, lH); 7.91 (d, 2H).
The products of Examples 2, 76, 88, 89, 98,
219, 220, 222 and 225 and the following products were
prepared by an analogous procedure:
Example 3:
Methyl 2-[[[2-propyl-1- r ( 4-(methoxycarbonyl)phenyl~-
methyll-lH-imidazol-5-~llmethyl]aminolbenzoate
Brown oil
lH NMR (300 MHz; CDCl3; ppm)
0.94 (t, 3H); 1.73 (m, 2H); 2.53 (t, 2H); 3.77 (s, 3H);
- : ~, ... ,. . .. . - :
.. ..
- 27 - 20~28~2
3.91 (s, 3H); 4.18 (d, 2H); 5.18 (s, 2H); 6.58 - 6.67
(m, 2H); 6.92 (d, 2H); 7.05 (s, lH); 7.28 - 7.33 (m,
lH); 7.68 (t, lH); 7.82 (d, lH); 7.90 (d, 2H).
05 Example 4:
2.2-Dimethyl-1,3-dioxolan-4-ylmethyl 2-~ r r 2-butyl-l-
r (4-(phenylmethoxycarbonyl~phenyl)methylI-lH-imidazol-
; 5-ylImethyl]aminoIbenzoate
Oil
lH NMR (300 MHz; CDCl3; ppm)
0.88 (t, 3H); 1.33 (m, 2H); 1.37 (s, 3H); 1.43 (s, 3H);
1.72 (m, 2H); 2.55 ~t, 3H); 3.82 (m, lH); 4.10 (m, lH);
4.25 (m, 4H); 4.35 (m, lH); 5.18 (s, 2H); 5.35 (s, 2H);
15 6.62 (m, 2H); 6.93 (d, 2H); 7.04 (s, lH); 7.26 - 7.46
(m, 6H); 7.64 (t, lH); 7.85 (d, lH); 7.94 (d, 2H).
Example 5:
20 Phenylmethyl 2-[[[2-butyl-1- r ( 4-(1.1-dimethylethoxy-
carbonyl)phenyl)methyll-lH-imidazol-5-yllmethyllamino]-
benzoate
Orange oil
; lH NMR (300 MHz; CDCl3; ppm)
-~ 25 0.88 (t, 3H); 1.32 (m, 2H); 1.56 (s, 9H); 1.73 (m, 2H);
2.56 (m, 2H); 4.18 (d, 2H); 5.18 (s, 2H); 5.23 (s, 2H);
" 6.60 (m, 2H); 6.89 (d, 2H); 7.03 (s, lH); 7.37 (m, 6H);
7.70 (t, lH); 7.90 (m, 3H).
, ~ .
-` 30 Example 6:
Methyl 2-r r r2-butyl-4-chloro-l-[ (4-(methoxycarbonvl~-
phenyl)methylI-lH-imidazol-5-yl]methyl~inol~3.5-
dichlorobenzoate
Yellow oil
,,: :, ,- : .- .,: ,, ,. ... :
.: -, . .~:: . .:. ~ . :
~ , .: . . .. , . . , : , .
- 28 - ~ 2
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.28 (m, 2H); 1.66 (m, 2H); 2.55 (t, 2H);
3.85 (s, 3H); 3.91 (s, 3H); 4.12 (d, 2H); 5.28 (s, 2H);
6.71 (t, lH); 6.98 (d, 2H); 7.40 (d, lH); 7.78 (d, lH);
05 7.97 (d, 2H).
Example 7:
Methyl 2-[[[2-butyl-4-chloro-1-[~4-(methoxycarbonyl)-
phenyl)methyl~-lH-imidazol-s-yl~methylLamino]-3-methyl-
benzoate
Pale yellow oil
lH NMR (300 MHz; dimethyl sulfoxide; ppm)
0.79 (t, 3H); 1.24 (m, 2H); 1.48 (m, 2H); 2.25 (s, 3H);
2.50 (t, 2H); 3.73 (s, 3H); 3.83 (s, 3H); 4.03 (d, 2H);
5.30 (s, 2H); 6.40 (t, lH); 6.85 (t, lH); 7.06 (d, 2H);
7.29 (d, lH); 7.59 (d, lH); 7.90 (d, 2H).
Example 8:
Methyl N-r[2-butyl-4-chloro-1-[(4-(methoxycarbonyl)-
phenyl)methyll-lH-imidazol-s-yllmethyl]-N-methyl-2
aminobenzoate
Yellow oil
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.34 (m, 2H); 1.68 (m, 2H); 2.57 (t, 2H);
2.61 (s, 3H); 3.85 (s, 3H); 3.89 (s, 3H); 3.93 (s, 2H);
5.32 (s, 2H); 6.88 - 6.99 (m, 4H); 7.35 (t, lH); 7.68
(d, lH); 7.88 (d, 2H).
~ 30
..~
Example 74:
Pentyl 2- r r r 2-butyl-4-chloro-1-[(4-(phenylmethoxycar-
bonyl~phenyl)methyll-lH-imidazol-s-yl~methyllaminol-
benzoate
::
:.
, ; : : , . . :,
: . ~
- 29 -
lH NMR (300 MHz; CDCl3; ppm)
0.88 (m, 6H); 1.28 - 1.38 (m, 6H); 1.60 - 1.71 (m, 4H);
2.51 (t, 2H); 4.12 (t, 2H); 4.18 (d, 2H); 5.19 (s, 2H);
5.35 (s, 2H); 6.60 (t, lH); 6.67 (d, lH); 6.90 (d, 2H);
05 7.32 - 7.45 (m, 5H); 7.75 (t, lH); 7.79 (d, lH); 7.90
(d, 2H).
Example 75:
Methyl 2- r r r 2-butyl-l- r ( 4-(methoxycarbonyl)phenyl)-
methyl]-4-methylthio-lH-imidazol-5-yl]methyllamino]-
benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.31 (m, 2H), 1.68 (m, 2H); 2.46 (s, 3H);
2.54 (t, 2H); 3.75 (s, 3H); 3.91 (s, 3H); 4.30 (d, 2H);
5.19 (s, 2H); 6.60 (t, lH); 6.80 (d, lH); 6.89 (dl 2H);
7.32 (m, lH); 7.67 (t, lH); 7.82 (m, 3H).
Example 77:
(~Dipropylamino)carbonyl)methyl 2-~[[2-butyl-1-[4-
((methoxycarbonyl)pheny])methyll-lH-imidazol-5-yl~-
methyl]amino]benzoate
H NMR (300 MHz; CDCl3; ppm)
0.92 (m, 9H); 1.33 (m, 2H); 1.52 - 1.74 (m, 6H); 2.55
(t, 2H); 3.17 (t, 2H); 3.30 (t, 2H); 3.90 (s, 3H); 4.17
(d, 2H); 4.83 (s, 2H); 5.19 (s, 2H); 6.63 (m, 2H); 6.92
(d, 2H); 7 (s, lH); 7.33 (t, lH); 7.61 (t, lH); 7.90
(d, 2H); 7.96 (d, lH).
Example 78:
((N.N-Dipropylamino)carbonyl)methyl 2-r r r2 - butyl-l-r4-
((benzyloxycarbonyl ! phenyl~methyll-lH-imidazol-5-yll-
methyl~aminolbenzoate
- ,: :: . , . . ::; : . -:;
. - ,, , . ,: : , ~ .
- . . .: . .. . . .. . .
:
- 30 - ~ 2 ~
lH NMR (300 MHz; CDCl3; ppm)
0.84 - 0.98 (m, 9H); 1.35 (m, 2H); 1.53 - 1.71 (m, 6H);
2.55 (t, 2H); 3.15 (t, 2H); 3.29 (t, 2H); 4.16 (d, 2H);
4.79 (s, 2H); 5.19 (s, 2H); 5.35 (s, 2H); 6.60 (m, 2H);
05 6.91 (d, 2H); 7 (s, lH); 7.16 - 7.45 (m, 6H); 7.59 (t,
lH); 7.93 - 7.97 (m, 3H).
Example 79:
((N,N-Diethylamino~carbonyl~methy~ ~-r r r2-butyl-l-[4-
((benzyloxycarbonyl)phenyl)methyll-lH-imidazol-5-yll-
methyllamino]benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.14 (t, 3H); 1.23 (t, 3H); 1.35 (m, 2H);
1.68 (m, 2H); 2.54 (t, 2H); 3.25 (q, 2H); 3.38 (q, 2H);
4.16 (d, 2H); 4.78 (d, 2H); 5.19 (s, 2H); 5.35 (s, 2H);
6.61 (m, 2H); 6.90 (d, 2H); 7 (s, lH); 7.16 - 7.45 (m,
6H); 7.58 (t, lH); 7.95 (m, 3H).
Example 80:
- l-((N,N-Diethylamino)carbonyl)ethyl 2-[~r2-butyl-1- r 4~
(Lbenzyloxycarbonyl~phenyl~methyl~-lH-imidazol-5
methyllamino]benzoate
lH NMR (300 MHz; CDCl3; ppm)
~ 0.87 (t, 3H); 1.12 (t, 3H); 1.24 (t, 3H); 1.33 (m, 2H);
; 1.47 (d, 3H); 1.68 (m, 2H); 2.55 (t, 2H); 3.23 - 3.52
(m, 4H); 4.14 (d, 2H); 5.17 (s, 2H); 5.35 (s, 2H); 5.40
(q, lH); 6.60 (m, 2H); 6.93 (d, 2H); 7 (s, lH); 7.16 -
7.45 (m, 6H); 7.57 (t, lH); 7.94 (m, 3H).
':
. . :~ ., . . . .,, . : ,
, :. ` ,: '' ,, . : ~, r
`, - . ', :,, ,.,, ' . '
. :- .:, : ` '' ` .. . ,:, . '~
g ~ ~
- 31 -
Example 81:
((N,N-Di(2-hydroxyethyl)amino)carbonyl)methyl 2-[ r ~ 2-
butyl-l- r 4-((benzyloxycarbonyl)phenyl)methyl]_lH_
05 imidazol-5-yl~methyllaminolbenzoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.34 (m, 2H); 1.67 (m, 4H); 2.54 (t, 2H);
3.43 (t, 2H); 3.54 (t, 2H); 3.81 (t, 2H); 3.86 (t, 2H);
4.15 (d, 2H); 4.89 (s, 2H); 5.16 (s, 2H); 5.35 (s, 2H);
6.60 (m, 2H); 6.90 (d, 2H); 7 (s, lH); 7.26 - 7.45 (m,
7H); 7.93 (m, 3H).
Example 82:
((N-Hethyl-N-(2-hydroxyethyl)amino)carbonyl)methyl 2-
[[r2-butyl-1-~4-((benzyloxycarbonyl)phenyl~methyl]-lH-
imidazol-5-yl~methyl]aminolbenzoate
H NMR (300 MHz; CDCl3; ppm)
0.77 (t, 3H); 1.22 (m, 2H); 1.47 (m, 2H); 2.49 (m, 2H);
2.81 (s, 1.5H); 2.95 (s, 1.5H); 3.45 (m, 2H); 3.54 (m,
2H); 4.32 (d, 2H); 4.74 (s, lH); 4.87 (s, lH); 5.32 (s,
2H); 5.34 (s, 2H); 6.55 (m, 2H); 6.81 (d, 2H); 6.88 (s,
lH); 6.g5 (m, 2H); 7.40 (m, 4H); 7.58 (t, lH); 7.72 (d,
lH); 7.85 (m, 2H).
Example 83:
Pentyl 6-chloro-2- r [ r 2-butyl-1- r ( 4-(methoxycarbonyl)-
phenyl)methyl~-lH-imidazol-5-yllmethyllamino]benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.36 (m, 6H); 1.65 (m, 4H); 2.58 (t, 2H);
3.91 (s, 3H); 4.09 (d, 2H); 4.25 (t, 2H); 5.16 (s, 2H);
5.93 (t, lH); 6.51 (d, lH); 6.71 (d, lH); 6.95 (d, 2H);
7.02 (s, lH); 7.11 (t, lH); 7.96 (d, 2H).
: . .:: .. ~ . , : , :. - : :, ,: ~: . , . . , . -:, :
,, . , , , , . -. ,
: : . : : , : : . :: : , :: -:: : ; .: : .
::. : : ~ : :: :,: ,, , ~ ::: -
- 32 ~ 2~2~
Example 84:
Ethyl [ [2-r r [2-butyl-1-[(4-(phenylmethoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yl]methyllaminolphenyll-
05 carbonyloxylacetate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.29 (m, 5H); 1.69 (m, 2H); 2017 (s, 2H);
2.58 (t, 2H); 4.22 (m, 4H); 4.71 (s, 2H); 5.17 (s, 2H);
5.35 (s, 2H); 6.61 (m, 2H); 6.90 (d, 2H); 7.03 (s, lH);
7.38 (m, 4H); 7.46 (t, lH); 7.93 (m, 3H).
Example 85:
1- r 2- r r r 2-Butyl-1-~(4-(phenylmethoxycarbonyl)phenyl)-
methyll-lH-imidazol-5-yllmethyllamino1phenylcarbonyl-
oxylethyl 2-ethylbutanoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (m, 9H); 1.33 (m, 2H); 1.46 - 1.74 (m, 9H); 2.18
(m, lH); 2.23 (t, 2H); 4.15 (d, 2H); 5.17 (s, 2H); 5.35
(s, 2H); 6.65 (m, 2H); 7.02 (d, 2H); 7.05 (t, 2H);
7.26 - 7.44 (m, 6H); 7.69 (t, lH); 7.80 (m, lH); 7.96
(d, 2H).
Example 86:
~ l-r2-r r [2-Butyl-l-r (4-(phenylmethoxycarbonyl)phenyl)-
methyll-lH-imidazol-5-yl~methyllamino]phenylcarbonyl-
oxy]ethyl cvclo~entylcarboxylate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.36 (m, 2H); 1.2 - 1.8 (m, 13H); 2.5 (t,
2H); 2.67 (q, lH); 4.17 (d, 2H); 5.17 (s, 2H); 5.35 (s,
2H); 6.61 (m, 2H); 6.90 (d, 2H); 7.02 (m, 2H); 7.16 -
7.42 (m, 6H); 7.7 (t,-lH); 7.82 (m, lH); 7.93 (d, 2H).
'~9~
- 33 -
Example 87:
Pentyl 2-r r r2-butyl-l-r (4-(methoxycarbonyl!phenyl)-
methyll-lH-imidazol-5-yl]methyllaminol-6-methylbenzoate
05 lH NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.38 (m, 6H); 1.64 (m, 4H); 2.40 (s, 3H);
2.54 (t, 2H); 3.90 (s, 3H); 4.12 (d, 2H); 4.19 (t, 2H);
5.18 (s, 2H); 6.50 (d, 2H); 6.68 (t, lH); 6.92 (d, 2H);
7.03 (s, lH); 7.14 (t, lH); 7.92 (d, 2H).
Bxample 90:
-r2-r r [2-Butyl-l-r ~4-(phenylmethoxycarbonyl)phenyl~-
methyl]-lH-imidazol-5-yllmethyl~amino~phenylcarbonyl-
oxy]ethyl cyclopentylacetate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.15 (m, 2H); 1.35 (m, 2H); 1.45 - 1.90
(m, 12H); 2.1 - 2.35 (m, 3H); 2.56 (t, 2H); 4.17 (d,
2H); 5.18 ~s, 2H); 5.35 (s, 2H); 6.58 (m, 2H); 6.93 (d,
20 2H); 7.05 (m, 2H); 7.26 - 7.45 (m, 5H); 7.67 (t, lH);
7.80 (d, lH); 7.93 (d, 2H).
Example 91:
1- r 2- r r r 2-Butyl~ ( 4-(phenylmethoxycarbonyl)phenyl)-
methylj-lH-imidazol-5-yllmethyllamino~phenylcarbonyl-
oxy]ethyl cyclohexylcarboxylate
lH NMR (300 MHz; CDCl3; ppm)
; 0.85 (t, 3H); 1.21 - 1.74 (m, 15H); 1.86 (m, 2H); 2.26
30 (m, lH); 2.53 (t, 2H); 4.15 (d, 2H); 5.18 (s, 2H); 5.35
(s, 2H); 6.61 (m, 2H); 6.9 (d, 2H); 7.1 (m, 2H); 7.15 -
7.45 (m, 6H); 7.65 (t, lH); 7.8 (m, lH); 7.93 (d, 2H).
:
; 35
:`
'i~
: : , , ::: . . .~ : ::. ::
- 34 - 2~ 92~ ~ 2
Example 92:
l- r 2- r r ~ 2-Butyl-l- r ~ 4-(phenylmethoxycarbonyl~phenyl)-
methyll-lH-imidazol-5-yl]methyl]amino]phenylcarbonyl-
05 oxy]ethyl 2 r 2-dimethylpropionate
1H NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.19 (s, 9H); 1.36 (m, 2H); 1.54 (d, 3H);
1.67 (m, 2H); 2.55 (t, 2H); 4.17 (d, 2H); 5.17 (s, 2H);
5.35 (s, 2H); 6.70 (m, 2H); 6.90 (d, 2H); 7.02 (m, 2H);
10 7.26 - 7.45 (m, 7H); 7.7 (t, lH); 7.82 (m, lH); 7.96
(d, 2H).
Example 93:
r2-r r r2-Butyl-l-r ~4-~phenylmethoxycarbonyl~phenyl)-
methyll-lH-imidazol-5-yl]methyl]amino]phenylcarbonyl-
oxylmethyl 2.2-dimethylpropionate
H NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.33 (m, 2H); 1.47 (s, 9H); 1.69 (m, 3H);
20 2.56 (t, 2H); 4.17 (d, 2H); 4.57 (s, 2H); 5.17 (s, 2H);
5.35 (s, 2H); 6.62 (m, 2H); 6.90 (d, 2H); 7.03 (s, lH);
7.30 - 7.50 (m, 5H); 7.53 (t, lH); 7.92 (m, 3H).
Example 94:
-~ r2-~ r r2-Butyl-1-r~4-(phenylmethoxycarbonyl~phenyl)-
methyl~-lH-imidazol--5-yllmethyllamino]phenylcarbonyl--
- oxylmethyl hexanoate
H NMR (300 MHz; CDCl3; ppm)
30 0.85 (m, 6H); 1.20 - 1.8 (m, lOH); 2.34 (t, 2H); 2.56
(t, 2H); 4.17 (d, 2H); 5.17 (s, 2H); 5.35 (s, 2H); 5.84
- (s, 2H); 6.59 (m, 2H); 6.90 (d, 2H); 7.03 (s, lH);
7.29 - 7.45 (m, 6H); 7.58 (t, lH); 7.84 (m, lH); 7~96
(d, 2H).
- . ~ ~. ,...... -
,. . . -: - ~
, . ": ...
- . . . . .
% ~ 2
- 35 -
Example 95:
2-(N,N-Diethylamino)ethyl 2- r [ [ 2-butyl-1-[(4-(phenyl-
methoxycarbonyl)phenyl)methyl]-lH-imidazol-5-yl~-
05 methyllamino1benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.05 (t, 6H); 1.27 (m, 2H); 1.65 (m, 2H);
2.59 (m, 6H); 2.78 (t, 2H); 4.08 - 4.26 (m, 4H); 5.18
(s, 2H); 5.35 (s, 2H); 6.62 (m, 2H); 6.91 (d, 2H); 7.03
10 (s, lH); 7.26 - 7.50 (m, 6H); 7.71 (t, lH); 7.83 (m,
lH); 7.93 (d, 2H).
Example 96:
l-Methylpentyl 2-r r r2-butyl-l-r (4-(phenylmethoxycar-
bonyl)phenyl)methyll-lH-imidazol-5-yllmethyl~amino1-
benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.24 - 1.38 (m, 9H); 1.68 (m, 4H); 2.54
20 (t, 2H); 4.16 (d, 2H); 4.98 (m, lH); 5.19 (s, 2H); 5.34
(s, 2H); 6.60 (m, 2H); 6.93 (d, 2H); 7.03 (s, lH);
7.29 - 7.42 (m, 6H); 7.78 (t, lH); 7.86 (m, lH); 7.94
(d, 2H).
Exam~le 97:
.~
l-Methyl-2-oxobutyl 2-r[r2-butyl-1-[(4-(phenylmethoxy-
carbonyl)phenyl)methyll-lH-imidazol-5-yllmethyllamino~-
;- benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.84 (m, 3H); 1.05 (m, 3H); 1.30 - 1.71 (m, 7H); 2.54
(m, 4H); 4.18 (d, 2H); 5.17 (m, 3H); 5.35 (s, 2H); 6.62
(m, 2H); 6.93 (s, 2H); 7.03 (s, lH); 7.26 - 7.41 (m,
5H); 7.45 (t, lH); 7.93 (m, 3H).
~'',
- .,.
. - ,. . .... .. ..
-~
-: : : ~: , ,, .~. . ,: ..
. .
- 36 - 2~928~
Example 99:
2-Oxobutyl 2-[~[2-butyl-1- r ( 4-(phenylmethoxycarbonyl)-
phenyl)methyl]-1~-imidazol-5-yllmethyllamino~benzoate
os lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.12 (t, 3H); 1.30 (m, 3H); 1.69 (m, 2H);
2.43 (m, 2H); 2.55 (m, 2H); 4.17 (d, 2H); 4.74 (s, 2H);
5.17 (s, 2H); 5.35 (s, 2H); 6.59 (m, 2H); 6.90 (d, 2H);
7.03 (s, lH); 7.30 - 7.42 (m, 5H); 7.46 (t, lH); 7.91
(m, 3H).
Example 100:
Ethyl 2-[ r 2-[ r r 2-butyl-1-[(4-(phenylmethoxycarbonyl)-
phenyl)methyl]-lH-imidazol-5-yllmethyllamino]phenyll-
carbonyloxy]propionate
H NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.23 - 1.40 (m, 5H); 1.54 (d, 3H); 1.69
(m, 2H); 2.55 (t, 2H); 4.17 (m, 4H); 5.13 (m, 3H); 5.35
(s, 2H); 6.59 (m, 2H); 6.64 (d, 2H); 7.02 (s, lH);
7.27 - 7.40 (m, 6H); 7.44 (t, lH); 7.93 (m, 3H).
Example 101:
Pentyl [[2-[ r r2-butyl-l-r (4-(phenylmethoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yllmethyl]amino]phenyll-
~i carbonyloxy]acetate
lH NMR (300 MHz, CDCl3; ppm)
0.87 (m, 6H); 1.31 (m, 6H); 1.62 (m, 4H); 2.56 (t, 2H);
4.16 (m, 4H); 4.67 (s, 2H); 5.15 (s, 2H); 5.42 (s, 2H);
~ 6.63 (m, 2H); 6.90 (d, 2H); 7.03 (s, lH); 7.27 - 7.46
; (m, 6H); 7.50 (t, lH); 7.95 (m, 3H).
- ,: ~...... . ..
- - .
' , ~ . . ' .. ''. ' 1' ' ,
,, ,, , -
2 ~
- 37 -
Example 102:
2-Phenylethyl 2-[ r [ 2-butyl-1- r ( 4-(phenylmethoxycar-
bonyl)phenyl)methyll-lH-imidazol-5-yl]methyllamino~-
os benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.33 (m, 2H); 1.69 (m, 2H); 2.55 (t, 2H);
2.98 (t, 2H); 4.16 (d, 2H); 4.35 (t, 2H); 5.17 (s, 2H);
5.33 (s, 2H); 6.60 (m, 2H); 6.90 (d, 2H); 7.03 (s, lH);
7.2 - 7.45 (m, llH); 7.67 (t, lH); 7.77 (m, lH); 7.93
(d, 2H).
Example 103:
Phenyl 2- r r r 2-butyl-1- r ( 4-(phenylmethoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yllmethYllamino]benzoate
H NMR (300 MHz; CDCl,; ppm)
0.86 (t, 3H); 1.29 (m, 2H); 1.65 (m, 2H); 2.52 (t, 2H);
4.20 (d, 2H); 5.15 (s, 2H); 5.35 (s, 2H); 6.75 (m, 2H);
6.90 (d, 2H); 7.03 (s, lH); 7.08 (m, 2H); 7.25 - 7.45
(m, 9H); 7.65 (t, lH); 7.91 (d, 2H); 8.05 (m, lH).
~i Example 104:
2-Methoxyethyl 2-r r r2-butyl-1-r~4-(phenylmethoxycar-
bonyl)phenyl~methyll-lH-imidazol-5-yl]methyl]
benzoate
H NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.31 (m, 2H); 1.67 (m, 2H); 2.56 (t, 2H);
3.38 (s, 3H); 3.64 (t, 2H); 4.17 (d, 2H); 4.30 (t, 2H);
5.18 (s, 2H); 5.35 (s, 2H); 6.60 (m, 2H); 6.94 (d, 2H);
7.04 (s, lH); 7.25 - 7.45 (m, 6H); 7.64 (t, lH); 7.86
(m, lH); 7.93 (d, 2H).
.
. .
:- , : " , -
' . . , , .,; ~- , ' ,
- " ~: :' l ' :
~: : . -:.
:., - :
'~3~
- 38 -
Example 105:
Decyl 2-~ r [ 2-butyl-1- r ~ 4-(phenylmethoxycarbonyl)-
phenyl)methylJ-lH-imidazol-5-ylJmethyl]amino~benzoate
05 lH NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.30 (m, 20H); 1.66 (m, 2H); 2.55 (t,
2H); 4.14 (m, 4H); 5.18 (s, 2H); 5.33 (s, 2H); 6.57 (m,
2H); 6.90 (d, 2H); 7.03 (s, lH); 7.26 - 7.45 (m, 4H);
7.7 (t, lH); 7.85 (m, lH); 7.94 (d, 2H).
Example 106:
Heptyl 2- r ~ [ 2-butyl-1- r ( 4-(phenylmethoxycarbonyl~-
phenyl)methyll-lH-imidazol-5-yllmethyllamino]benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (m, 6H); 1.30 (m, lOH); 1.66 (m, 4H); 2.55 (t,
2H); 4.14 (m, 4H); 5.18 (s, 2H); 5.35 (s, 2H); 6.57 (m,
2H); 6.90 (d, 2H); 7.03 (s, lH); 7.28 - 7.45 (m, 6H);
7.27 (t, lH); 7.84 (m, lH); 7.93 (d, 2H).
Example 107:
:,
3-Methylbutyl 2- r r r 2-butyl-1- r 14-(phenylmethoxycar-
bonyl~phenyl)methyl]-lH-imidazol-5-yllmethylJamino]-
benzoate
H NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 0.93 (d, 6H); 1.30 (m,~2H)~ 1.55 (m, 5H);
~` 2.55 (t, 2H); 4.18 (m, 4H); 5.18 (s, 2H); 5.35 (s, 2H);
6.57 (m, 2H); 6.91 (d, 2H); 7.04 (s, lH); 7.27 - 7.45
(m, 6~); 7.73 (t, lH); 7.83 (m, lH); 7.96 (d, 2H).
.
.
.. . .
: .
2~2~
- 39 -
Example 108:
1-Methylethyl 2-[[[2-butyl-1-r(4-rphenylmethoxycar-
bonyl)phenyl)methyl]-lH-imidazol-5-yl]methyl]aminol-
05 benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.29 (d, 6H); 1.35 (m, 2H); 1.66 (m, 2H);
2.54 (t, 2H); 4.17 ~d, 2H); 5.06 (m, lH); 5.18 (s, 2~);
5.30 (s, 2H); 6.59 (m, 2H); 6.90 (d, 2H); 7.03 (s, lH);
7.26 - 7.45 (m, 6H); 7.75 (t, lH); 7.85 (m, lH); 7.93
(d, 2H).
Example 109:
:
Cyclopropylmethyl 2-[[[2-butyl-1-r(4-(phenylmethoxy-
, ca~bonyl)phenyl)methyll-lH-imidazol-5-yllmethyl]aminol-
-~ benzoate
H NMR (300 MHz; CDCl3; ppm)
0.29 (m, 2H); 0.55 (m, 2H); 0.87 (t, 3H); 1.1 - 1.38
(m, 3H); 1.68 (m, 2H); 2.52 (t, 2H); 3.97 (d, 2H); 4.17
(d, 2H); 5.18 (s, 2H); 5.35 (s, 2H); 6.60 (m, 2H); 6.95
(d, 2H); 7.03 (s, lH); 7.26 - 7.45 (m, 6H); 7.69 (t,
lH); 7.90 (m, lH); 7.93 (d, 2H).
, . .
Example 110:
2-Methylpropyl 2-r r r2-butyl-l-[ (4-lphenylmethoxycar-
bonyl)phenyl~methyll-lH-imidazol-5-yllmethyl]aminol-
benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 0.96 (d, 6H); 0.33 (m, 2H); 1.69 (m, 2H);
2.0 (m, lH~; 2.55 (t, 2H); 3.93 (d, 2H); 4.17 (d, 2H);
5.19 (s, 2H); 5.34 (s, 2H); 6.60 (m, 2H); 6.91 (d, 2H);
7.04 (s, lH); 7.28 - 7.45 (m, 6H); 7.72 (t, lH); 7.87
tm, lH); 7.93 (d, 2H).
,: .. ~ . : .. ~.; .
. . . :
: . . ., , :- ::
. : . ., ,: :: .: . . ..
,
`'J ~ t'`~ '.'
-- 40 --
Example 111:
Hexadecyl 2-~r2-butyl-1-r~4-(phenylmethoxycarbonyl)-
phenyl~methyl]-lH-imidazol-5-yl]methyllaminolbenzoate
05 lH NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.20 - 1.74 (m, 32H); 2.55 (t, 2H); 4.16
(m, 4H); 5.18 (s, 2H); 5.35 (s, 2H); 6.59 (m, 2H); 6.95
(d, 2H); 7.03 (s, lH); 7.26 - 7.44 (m, 6H); 7.72 (t,
lH); 7.84 (m, lH); 7.93 (d, 2H). ;-~
Example 112: ;
.~ :
Butyl 2- r r r 2-butyl-1- r ( 4-(phenylmethoxycarbonyl~-
phenyl)methyl~-lH-imidazol-5-yllmethyllamino]benzoate
15 lH NMR (300 MHz; CDC13; ppm)
0.85 (t, 3H); 0.95 (t, 3H); 1.38 (m, 4H); 1.67 (m, 4H);
2.55 (t, 2H); 4.17 (m, 4H); 6.19 (s, 2H); 5.35 (s, 2H);
6.60 (m, 2H); 6.91 (d, 2H); 7.04 (s, lH); 7.27 - 7.45
(m, 6H); 7.72 (t, lH); 7.82 (m, lH); 7.95 (d, 2H).
Example 113:
Ethyl 2-r r r2-butyl-l-r (4-(ethoxycarbonyl)phenyl)-
;~ methyll-lH-imidazol-5-yl]methyl]aminolbenzoate
` 25 lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.36 (m, 8H); 1.69 (m, 2H); 2.55 (t, 2H);
4.19 (m, 4H); 4.37 (q, 2H); 5.18 (s, 2H); 6.60 (m, 2H);
6.90 (d, 2H); 7.04 (s, lH); 7.30 (m, lH); 7.74 (t, lH);
7.84 - 7.92 (m, 3H).
Example 114:
Pentyl 2-r[r2-butyl-l-r(4-(methoxycarbonyl~phenyl)-
methyl~-lH-imidazol-5-yl1methyl]aminolbenzoate
lH NMR (300 MHz; CDCl~; ppm)
.
" ' , ' .,` , . - :: ' ' -
': : ,'~ ' ', '
~9~
- 41 -
0.85 (m, 6H); 1.36 (m, 6H); 1.74 (m, 4H); 2.55 (t, 2H);
3.90 (s, 3H); 4.16 (m, 4H); 5.19 (s, 2H); 6.64 (m, 2H);
6.94 (d, 2H); 7.04 (s, lH); 7.30 (m, lH); 7.73 (t, lH);
7.83 - 7.92 (m, 3H).
05
Example 115:
:
Pentyl 2- r [ [ 1- r ( 4-(phenylmethoxycarbonyl~phenyl)-
methyl]-2-propyl-lH-imidazol-5-yl~methyllami~o]benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.90 (m, 6H); 1.40 (m, 4H); 1.64 (m, 4H); 2.53 (t, 2H);
4.16 (m, 4H); 5.18 (s, 2H); 5.35 (s, 2H); 6.59 (m, 2H);
6.93 (d, 2H); 7.04 (s, lH); 7.28 - 7.45 (m, 6H); 7.72
' (t, lH); 7.85 (m, lH); 7.96 (d, 2H).
Example 116:
.,
Methyl 2-[[[1-[(4-(methoxycarbonyl~phenyl)methyll-2-
propyl-lH-imidazol-5-yllmethyllamino~-4-nitrobenzoate
lH NMR (300 MHz; CDCl3; ppm)
0.95 (t, 3H); 1.74 (m, 2H); 2.56 (t, 2H); 3.81 (s, 3H);
4.02 (s, 3H); 4.28 (d, 2H); 5.17 (s, 2H); 6.91 (d, 2H);
7.10 (s, lH); 7.35 (m, lH); 7.74 (m, lH); 7.92 (m, 4H).
:;
Example 117:
Methyl 2- r [ r 2-butyl-1-[(4-((1~1-dimethylethoxy)car-
, bonyl)phenyl)methyl]-lH-imidazol-5-yllmethyllaminol-4-
; nitrobenzoate
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.35 (m, 2H); 1.58 (s, 9H); 1.69 (m, 2H);
2.58 (t, 2H); 3.81 (s, 3H); 4.26 (d, 2H); 5.16 (s, 2H);
; 6.87 (d, 2H); 7.09 (s, lH); 7.37 (m, lH); 7.47 (m, lH);
7.82 - 7.95 (m, 4H).
. .. : : ., , .:
- , .: ,, : ,
.:; : . .... . : -
: . ..
. , :
2 ~
- 42 -
Example 118:
,
1- r 2- r r r 2-Butyl-l- r ( 4-(phenylmethoxycarbonyl)phenyl)-
methyl~-lH-imidazol-5-yl1methyllamino~phenylcar~onyl-
os oxy]ethyl hexanoate
H NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.31 (m, 6H); 1.52 (d, 3H); 1.62 (m, 4H);
2.30 (t, 2H); 2.55 (t, 2H); 4.16 (d, 2H); 5.18 (s, 2H);
5.35 (s, 2H); 6.56 (m, 2H); 6.90 (d, 2H); 7.03 (m, 2H);
10 7.27 - 7.45 (m, 6H); 7.66 (t, lH); 7.82 (m, lH); 7.93
(d, 2H).
Example 119:
15 1.1-Dimethylethyl 2-[[[2-butyl-1-r(4-(phenylmethoxy-
carbonyl)phenyl)methyl]-lH-imidazol-5-yllmethyllaminl-
benzoate
H NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.25 (m, 2H); 1.44 ts, 9H); 1.66 (m, 2H);
20 2.55 (t, 2H); 4.18 (d, 2H); 5.19 (s, 2H); 5.35 (s, 2H);
6.55 (m, 2H); 6.90 (d, 2H); 7.04 (s, lH); 7.2 - 7.45
(m, 6H); 7.76 (m, 2H); 7.96 (d, 2H).
: . =
Example 120:
Ethyl 2- r r l2-butyl-1-~(4-(phenylmethoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yl]methyllaminolbenzoate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.32 (m, 5H); 1.71 (m, 2H); 2.57 (t, 2H);
30 4.15 (m, 4H); 5.18 (s, 2H); 5.35 (s, 2H); 6.59 (m, 2H);
6.90 (d, 2H); 7.04 (s, lH); 7.25 - 7.45 (m, 6H); 7.71
(t, lH); 7.81 (m, lH); 7.92 (d, 2H).
:
:, : , .
. ` . `.~ '
~2~2
- 43 -
Example 121:
1-((Pentylcarbonyl)oxy)ethyl 2-[t[2-butyl-l-r~4-(meth-
oxycarbonyl~phenyl)methyll-lH-imidazol-5-yllmethyll-
05 amino]benzoate
1H NMR (300 MHz; CDCl3; ppm)
0.85 (t, 6H); 1.32 (m, 6H); 1.54 (d, 3H); 1.67 (m, 4H);
2.31 (t, 2H); 2.56 (t, 2H); 3.90 (s, 3H); 4.18 (d, 2H);
5.18 (s, 2H); 6.58 (m, 2H); 6.94 (d, 2H); 7.03 (m, 2H);
7.35 (m, lH); 7.66 (t, lH); 7.82 (m, lH); 7.92 (d, 2H).
Example 122:
.~
Pentyl 2-[[[2-butyl-1- r (4-~phenylmethoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yllmethyllaminolbenzoate
H NMR (300 MHz; CDCl3; ppm)
0.87 (m, 6H); 1.33 (m, 6H); 1.68 (m, 4H); 2.55 (t, 2H);
4.14 (m, 4H); 5.18 (s, 2H); 5.35 (s, 2H); 6.59 (m, 2H);
6.93 (d, 2H); 7.04 (s, lH); 7.26 - 7.45 (m, 6H); 7.72
(t, lH); 7.82 (m, lH); 7.93 (d, 2H).
Example 123:
1- r 2- r r r 2-Butyl-1- r r 4-(phenylmethoxycarbonyl)phenvl)-
methyl]-lH-imidazol-5-yl~methyllaminolphenylcarbonyl-
oxy]ethyl cyclohexylacetate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 0.95 (m, 2H); 1.10 - 1.39 (m, 4H); 1.52
(d, 3H); 1.57 (m, 9H); 2.17 (m, 2H); 2.55 (t, 2H); 4.17
(d, 2H); 5.17 (s, 2H); 5.35 (s, 2H); 6.56 (m, 2H); 6.90
(d, 2H); 7.02 (m, 2H); 7.15 - 7.45 (m, 6H~; 7.68 (t,
lH); 7.~2 (m, lH); 7.96 (d, 2H).
- . . .- : . -. ,
: - .: . . : .
- 44 - 2~2~2
Example 124:
Phenylmethyl 2- r [ [ 2-butyl-1-[(4-(pentoxycarbonyl~-
Phenyl)methyll-lH-imidazol-5-yl]methyllaminolbenzoate
05 lH NMR (300 MHz; CDCl3; ppm)
0.88 (m, 6H); 1.37 (m, 6H); 1.65 - 1.75 (m, 4H); 2.56
(t, 2H); 4.20 (d, 2H); 4.27 (t, 2H); 5.17 (s, 2H); 5.22
(s, 2H); 6.60 (t, lH); 6.64 (d, lH); 7.0 (s, lH);
~ 7.26 - 7.39 (m, 6H); 7.69 (t, lH); 7.88 - 7.93 (m, 3H).
-~ 10
Example 125:
Phenylmethyl 2-~ r r2-butyl-1-[(4-(methoxycarbonyl)-
phenyl~methyl]-lH-imidazol-5-yl~methyl]amino]benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.33 (m, 2H); 1.69 (m, 2H); 2.55 (t, 2H);
3.87 (s, 3H); 4.16 (d, 2H); 5.17 (s, 2H); 5.21 (s, 2H);
6.58 (t, lH); 6.64 (d, lH); 6.90 (d, 2H); 7.04 (s, lH);
7.26 - 7.41 (m, 6H); 7.66 (t, lH); 7.88 - 7.92 (m, 3H).
Example 126:
Phenylmethyl 2- r r r 2-butyl-1-~(4-~ethoxycarbonyl)-
phen~,rl)methyl]-lH-imidazol-5-yllmethyllaminolbenzoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.33 (m, 5H); 1.69 (m, 2H); 2~56 (t, 2H);
4.18 (d, 2H); 4.33 (q, 2H); 5.17 (s, 2H); 5.22 (s, 2H);
6.60 (t, lH); 6.64 (d, lH); 6.91 (d, 2H); 7.05 (s, lH);
7.26 - 7.41 (m, 6H); 7.70 (t, lH); 7.88 - 7.97 (m, 3H).
Example 127:
Phenylmethyl 2-r[[2-butyl-1-[(4-lbutoxycarbonyl~-
Phenyl)methyll-lH-imidazol-5-yl]methyllamino]benzoate
lH NMR (300 MHz; CDCl3; ppm)
~ ~ -
- 45 - 2~2832
0.83 - 0.98 (m, 6H); 1.28 - 1.48 (m, 4H); 1.65 - 1.73
(m, 4H); 2.56 (t, 2H); 4.16 (d, 2H); 4.26 (t, 2H); 5.17
(s, 2H); 5.21 (s, 2H); 6.57 (t, lH); 6.62 (d, lH); 6.90
(d, 2H); 7.04 (s, lH); 7.26 - 7.39 (m, 6H); 7.70 (t,
05 lH); 7.91 (m, 3H).
:
Example 128:
Phenylmethyl 2-r[[2-butyl-1-[(4-(hexadecyloxycarbonyl~-
phenyl~methyll-lH-imidazol-5-yllmethyl]aminoJbenzoate
H NMR (300 MHz; CDCl3; ppm)
0.88 (m, 6H); 1.25 - 1.41 (m, 28H); 1.64 - 1.76 (m,
4H); 2.56 (t, 2H); 4.18 (d, 2H); 4.26 (t, 2H); 5.17 (s,
2H); 5.22 (s, 2H); 6.58 (t, lH); 6.64 (d, lH); 6.90 (d,
2H); 7.04 (s, lH); 7.26 - 7.39 (m, 6H); 7.70 (t, lH);
7.88 - 7.93 (m, 3H).
Example 129:
Phenylmethyl 2-[[[2-butyl-1-[(4-(~2-methylpropyl~oxy-
carbonyl~phenyl)methyl]-lH-imidazol-5-yl]methyl]aminol-
benzoate
H NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 0.96 (d, 6H); 1.29 - 1.41 (m, 2H); 1.65 -
1.75 (m, 2H); 2.04 (m, lH); 2.56 (t, 2H); 4.05 (d, 2H);
4.18 (d, 2H); 5.18 (s, 2H); 5.22 (s, 2H); 6.60 (t, lH);
6.65 (d, lH); 6.91 (d, 2H); 7.04 (s, lH); 7.26 - 7.39
(m, 6H); 7.70 (t, lH); 7.89 - 7.94 (m, 3H).
Example 130:
.~
~ Phenyl~ethyl 2-r r r2-butyl-l-r (4-(cyclopropylmethoxy-
carbonyl)phenyl)methyll-lH-imidazol-5-yllmethyl]amino~-
benzoate
lH NMR (300 MHz; CDCl3; ppm)
. , .~
0.36 (q, 2H); 0.58 (q, 2H); 0.86 (t, 3H); 1.19 - 1.39
(m, 3H); 1.68 - 1.75 (m, 2H); 2.56 (t, 2H); 4.10 (d,
2H); 4.18 (d, 2H); 5.18 (s, 2H); 5.22 (s, 2H); 6.60 (t,
lH); 6.64 (d, lH); 6.91 (d, 2H); 7.04 (s, lH); 7.26 -
05 7.41 (m, 6H); 7.68 (t, lH); 7.89 - 7.96 (m, 3H).
Example 131:
:
Phenylmethyl 2- r r [ 2-butyl-1- r f 4-~(3-methylbutyl~oxy-
10 carbonyl)phenyl)methyll-lH--imidazol-5-yl~methyllamino]--
benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 0.94 (d, 6H); 1.25 - 1.41 (m, 2H); 1.59 -
1.80 (m, 5H); 2.56 (t, 2H); 4.18 (d, 2H); 4.30 (t, 2H);
5.17 (s, 2H); 5.22 (s, 2H); 6.60 (t, lH); 6.64 (d, lH);
6.90 (d, 2H); 7.04 (s, lH); 7.26 - 7.39 (m, 6H); 7.70
(t, lH); 7.88 - 7.93 (m, 3H).
Example 132:
Pentyl 2-r r r2-butyl-l-[ (4-cyanophenyl~methyll-lH-
imidazol-5-yl~methyllaminolbenzoate
H NMR (300 MHz; CDCl3; ppm)
0.84 - 0.95 (m, 6H); 1.31 - 1.42 (m, 6H); 1.64 - 1.75
(m, 4H); 2.52 (t, 2H); 4.15 (t, 2H); 4.20 (d, 2H); 5.19
(s, 2H); 6.62 (t, lH); 6.66 (d, lH); 6.90 (d, 2H); 7.07
(s, lH); 7.31 (t, lH); 7.47 (d, 2H); 7.68 (t, lH); 7.83
(d, lH).
Example 133:
Pentyl 2-[ r [ 2-butyl-1- r ( 4~ 1-dimethylethoxy)car-
bonyl~phenyl~methyll-lH-imidazol-5-yllmethyllaminol-4-
nitrobenzoate
lH NMR (300 MHz; CDCl3; ppm)
.'
- , . ...................... . .. . ~ .
: ~ ;
. ;~ . ' ~ ' ' .:` .'' ,: ' '
- 47 -
0.84 - 0.95 (m, 6H); 1.25 - 1.42 (m, 6H); 1.58 (s, 9H);
1.62 - 1.76 (m, 4H); 2.57 (t, 2H); 4.21 (t, 2H); 4.23
; (d, 2H); 5.13 (s, 2H); 6.88 (d, 2H); 7.08 (s, lH); 7.38
(d, lH); 7.45 (s, lH); 7.85 (d, 2H); 7.95 (d, 2H).
05
Example 221:
Ethyl 3-methyl-2- r r r 2- r [ r 2-butyl-1- r (4-(phenylmethoxy-
carbonyl)Dhenyl)methyl~-lH-imidazol-5-yllmethyllaminol-
phenyllcarbonyl]aminolbutanoate
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 0.97 (m, 6H); 1.32 (m, 5H); 1.70 (m, 2H);
2.20 (m, lH); 2.53 (t, 2H); 4.11 (d, 2H); 4.23 (m, 2H);
4.60 (m, lH); 5.19 (s, 2H); 5.35 (s, 2H); 6.51 (d, lH);
6.63 (t, 2H); 6.96 (d, 2H); 7.0 (s, lH); 7.26 (t, lH);
7.40 (m, 6H); 7.52 (t, 1~); 7.95 (d, 2H).
Example 9:
Methyl 2- r r r 2-butyl-4-chloro-1-[(4-(methoxycarbonyl)-
phenyl)methvll-lH-imidazol-5-yllmethyllaminol-3,4 5-
trimethoxvbenzoate
4.82 g (20-10-3 mol) of methyl 2-amino-3,4,5-
trimethoxybenzoate are added to a solution of 3.55 g
~`- 25 (9.06-10-3 mol) of methyl 4-[(2-butyl-4-chloro-5-
chloromethyl-lH-imidazol-l-yl)methyl]benzoate hydro-
chloride in 30 ml of N-methylpyrrolidone. The reaction
mixture is heated at 80 C for 5 hours. After the addi-
tion of 100 ml of water, the aqueous phase is extracted
with 2 times 60 ml of ethyl acetate. The organic
phases are washed with water until the pH of the wash-
; ings is neutral, dried over magnesium sulfate, filtered
and evaporated under reduced pressure. The oily resi-
due obtained is purified by chromatography using a
toluene/ethyl acetate mixture (85/15; v/v) as the
, , ... ...... , !
2 ~ 2
- 48 -
eluent to give 2.43 g (yield: 48%) of a yellow oil.
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.28 (m, 2H); 1.63 (m, 2H); 2.48 (t, 2H);
3.65 (s, 3H); 3.81 (s, 3H); 3.82 (s, 3H); 3.91 (s, 3H);
05 3.92 (s, 3H); 4.34 (s, 2H); 5.27 (s, 2H); 6.73 (s, lH);
6.98 (d, 2H); 7.17 (s, lH); 7.95 (d, 2H).
Example 10:
Methyl 2-[ r [2-butyl-4-chloro-1-[(4-(methoxycarbonyl)-
phenyl)methyl]-lH-imidazol-5-yl]~ethyllamino]benzoate
A suspension of 0.9 g (2.3-10-3 mol) of methyl
4-[(2-butyl-4-chloro-5-chloromethyl-lH-imidazol-1-yl)-
methyl]benzoate hydrochloride in 4.5 ml of methyl anth-
ranilate is heated at 120 C for 20 minutes. After the
addition of 15 ml of water and 15 ml of a saturated
solution of sodium bicarbonate, the reaction mixture is
extracted with 30 ml of ethyl acetate. The organic
phase is washed with water until the washings are neu-
tral, dried over magnesium sulfate and evaporated under
reduced pressure. The yellow oil obtained is purified
by chromatography on silica using a toluene/ethyl ace-
tate mixture (90/10; v/v) as the eluent to give 1.07 g
(yield: 90%) of a colorless oil.
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.34 (m, 2H); 1.66 (m, 2H); 2.52 (t, 3H);
3.76 (s, 3H); 3.91 (s, 3H); 4.21 (d, 2H); 5.30 (s, 2H);
6.62 (t, lH); 6.72 (d, lH); 6.93 (d, 2H); 7.31 - 7.39
(m, lH); 7.69 (m, lH); 7.81 (d, lH); 7.90 (d, lH).
The product of Example 56 and the following
product were obtained by a procedure analogous to the
preparation of Example 10:
.~,
;, . . .
: . ~ . ; ~ :: . . .
- , , ,.. . , ., . -;, ~,,: . . . ~ . .
,: ,,, ., , :.;: .. . . .
. .. :;
~9~2
- 49 -
Example 57:
Methyl 4-rr2-butyl-4-chloro-5-~((4-cyanophenyl)amino)-
methyll-lH-imidazol-l-yl]methyllbenzoate
05 lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.35 ~m, 2H); 1.67 (m, 2H); 2.55 (t, 2H);
3.91 (s, 3H); 4.18 (d, 2H); 4.45 (t, lH); 5.21 (s, 2H);
6.68 - 6.76 (m, 2H); 6.95 (d, 2H); 7.33 - 7.40 (m, 2H);
7.94 (d, 2H).
Example 11:
Ethyl N-rr2-butyl-4-chloro-1-r(4-(methoxycarbonyl)-
; phenyl)methyl}-lH-imidazol-5-yl]methyllindole-2-car-
boxylate
0.68 g (22.6-10-3 mol) of 80% sodium hydride
in oil is added in portions to a solution of 4.26 g
(22.5-10-3 mol) of ethyl indole-2-carboxylate in 50 ml
of anhydrous dimethylformamide. After stirring at room
20 temperature for 20 minutes, 4 g (11.26-10-3 mol) of
methyl 4-[(2-butyl-4-chloro-5-chloromethyl-lH-imidazol-
l-yl)methyl]benzoate hydrochloride are added. Stirring
is maintained for 4.5 hours. 400 ml of water are added
to the reaction mixture and several extractions are
carried out with ethyl acetate. The organic phases are
washed with water until the washings are neutral, dried
over magnesium sulfate and evaporated under reduced
pressure. The brown oil obtained is purified by chro-
matography on silica using a toluene/ethyl acetate
30 mixture (95/5; v/v) as the eluent to give 2.06 g
(yield: 36%) of the expected product.
M.p. = 136 C
The product of Example 12 was prepared by an
analogous procedure.
- , . . . . ..
. , , , :~ . . ::, , . ., - :.:
.. : - : : , :. .: :: ,:, .. : :: .. ::: , :., .:
.: , - . .. . :., : ::, :. ~ .. - . - : ;
- 50 -
Example 13:
Methyl 2-r r r4-chloro-2-propyl-1-[(4-(methoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yl]methyllamino]benzoate
05 2.93 g (7.7 10-3 mol) of methyl 4-[(4-chloro-5-
chloromethyl-2-propyl-lH-imidazol-1-yl)methyl]benzoate
hydrochloride are suspended in 30 ml of anhydrous
toluene. 2.6 g (17 10-3 mol) of methyl anthranilate
are added and the mixture is then refluxed for 3 hours,
with stirring. The reaction mixture is then poured
into a saturated solution of sodium bicarbonate. Ex-
traction is carried out with ethyl acetate. The
organic phases are washed with water until the washings
are neutral, dried over magnesium sulfate and concen-
trated. The oily residue obtained is purified by
chromatography on silica using a toluene/ethyl acetate
mixture (95/5; v/v) as the eluent to give 2.1 g (yield:
59%) of a beige solid.
M.p. = 108 C
The proclucts of Examples 14, 15, 17, 18, 21 and
22 and the following products were prepared by an ana-
logous procedure:
:
Example 16:
Methyl 3-r r ~2-butyl-4-chloro-1-[r4-(methoxycarbonyl~-
Dhenyllmethyll-lH-imidazol-5-yllmethyl]aminolnaphtha-
lene-2-carboxylate
~;
Yellow oil
lH NMR (300 MHz; CDCl3; ppm)
0.86 (t, 3H); 1.33 (m, 2H); 1.67 (m, 2H); 2.51 (t, 3H);
3.83 (s, 3H~; 3.92 (s, 3H); 4.30 (d, 2H); 5.29 (s, lH);
; 6.90 (m, 3H); 7.20 (m, lH); 7.39 (m, 2H); 7.58 (d, lH);
` 7.66 (d, lH); 7.84 (d, 2H); 8.41 (s, lH).
,, . - : :~ : :. : . :
: . , : ~ . ~,., : , , ; : :
- :. . ::. ,. : . . . .
- ,,:,, ::,~ ' :. :; ~ .
.. ..
5 1
Example 19:
Methyl 2-r[r2-butyl-4-iodo-1-r(4-(methoxycarbonyl)-
phenyl~methyl]-lH-imidazol-5-yl~methyl]amino]benzoate
05 Yellow oil
1H NMR (300 MHz; CDCl,; ppm)
0.85 (t, 3H); 1.28 (m, 2H); 1.68 (m, 2H); 2.55 (t, 2H);
3.77 (s, 3H); 3.91 (s, 3H); 4.18 (d, 2H); 5.23 (s, 2H);
6.64 (m, 2H); 6.89 (d, 2H); 7.33 (t, lH); 7.66 (t, lH);
7.80 (d, lH); 7.88 (d, 2H).
Example 20:
Methyl 2-[ r ~2-butyl-4-trifluoromethyl-1-r(4-(methoxy-
carbonyl)phenyl)methylI-lH-imidazol-5-ylImethyl]aminol-
benzoate
Colorless oil
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.34 (m, 2H); 1.71 (m, 2H); 2.59 (t, 2H);
20 3.78 (s, 3H); 3.91 (s, 3H); 4.32 (d, 2H); 5.22 (s, 2H);
6.64 (m, 2H); 6.92 (d, 2H); 7.31 (m, lH); 7.64 (t, lH);
7.83 (d, lH); 7.92 (d, 2H).
Example 215:
Methyl 4-rr2-butyl-5-r((2-(((3-(dimethylamino)propyl)-
amino)carbonyl~phenyl)amino~methylI-lH-imidazol-l-ylI-
` methylIbenzoate
; lH NMR (300 MHz; CDCl,; ppm)
30 0.86 (t, 3H); 1.32 (m, 2H); 1.70 (m, 4H); 2.27 (s, 6H);
; 2.48 (m, 4H); 3.44 (m, 2H); 3.88 (s, 3H); 4.12 (d, 2H);
5.21 (s, 2H); 6.59 (t, lH); 6.64 (d, lH); 6.94 (d, 2H);
7.0 (s, lH); 7.23 (t,-2H); 7.91 (d, 2H); 7.99 (t, lH);
8.27 (t, lH).
: "
:~ ~; .; : .. :: .. :, :
"
% ~
- ~2 -
Example 23:
Methyl 2-[[ r 2-butyl-4-chloro-1-~(4-carboxyphenyl~-
methyl]_1H_imidazol-5-yl]methyl]amino~benzoate
05 0.8 g (20 10-3 mol) of sodium hydroxide and 10
ml of water are added to a solution of 9 g (19 . 1 10-3
mol) of methyl 2-[[[2-butyl-4-chloro-1-[(4-(methoxy-
carbonyl)phenyl)methyl]-lH-imidazol-5-yl]methyl]amino]-
benzoate in 80 ml of methanol. The reaction mixture is
heated at 50C for 3.5 hours. The methanol is evapora-
ted off under reduced pressure and the residue is
diluted with 150 ml of water. The aqueous phase is
washed with 3 times 50 ml of ethyl acetate and then
acidified to pH 5 with 1 N hydrochloric acid and
extracted with 2 times 50 ml of ethyl acetate. The
organic phases are washed with water until the washings
are neutral, dried over magnesium sulfate, filtered and
evaporated under reduced pressure. The solid residue
is purified by chromatography on silica using a di-
chloromethane/methanol mixture (95/5; v/v) as the
~` eluent to give 5.1 g (yield: 58%) of a white solid.
M.p. = 181 C
' The products of Examples 24, 223 and 224 were
obtained by an analogous procedure.
- 25
Example 25:
.~' . .
Phenylmethyl 2-r[[2-butyl-l-r(4-carboxyphenyl)methyll-
lH-imidazol-5-yl]methyl~amino]benzoate
A solution of 2.6 g (4.7 10-3 mol) of phenyl-
methyl 2-[[[2-butyl-1-[(4-(1,1-dimethylethoxycarbonyl)-
phenyl)methyl]-lH-imidazol-5-yl]methyl]amino]benzoate
in 10 ml of trifluoroacetic acid is stirred at 0C for
3 hours. The trifluoroacetic acid is evaporated off
under reduced pressure. After the addition of 60 ml of
" ' ", ~ . " " ~ ' : ',
- 53 -
water to the residue and of sodium hydroxide to pH 6,
extraction is carried out with 2 times 30 ml of ethyl
acetate. The organic phase is washed with 2 times 10
ml of water, dried over magnesium sulfate, filtered and
05 evaporated under reduced pressure to give 2.4 g (yield:
100%) of a yellow foam.
M.p. = 90 C
The products of Examples 195 to 197 were pre-
pared by an analogous procedure.
Example 26:
2,2-Dimethyl-1,3-dioxolan-4-ylmethyl 2- r r r 2-butyl-1-
r (4-carboxyphenyl)methyll-lH-imidazol-5-yllmethyll-
amino]benzoate
0.39 g of 10~ palladium-on-charcoal is added
under a nitrogen atmosphere to a solution of 3.9 g
( 6 . 38 10-3 mol) of 2,2-dimethyl-1,3-dioxolan-4-ylmethyl
2-[[[2-butyl-1-[((4-phenylmethoxycarbonyl)phenyl)-
methyl]-lH-imidazol-5-yl]methyl]amino]benzoate in 150
ml of methanol. The reaction medium is then placed
,~
under a hydrogen atmosphere and stirred for 2.5 hours.
After filtration, the methanol is evaporated off under
reduced pressure. The residue obtained is purified by
- 25 chromatography on silica using a dichloromethane/metha-
nol mixture (90/10; v/v) as the eluent to give 2.3 g
~ (yield: 69~) of a white foam.
-~ M.p. = 92 C
The products of Examples 27 and 134 to 179 were
prepared by an analogous procedure.
:.
,
;:
- 54 -
Example 28:
2,3-Dihydroxypropyl 2- r [ r 2-butyl-1-[(4-carboxyphenyl~-
methyll-lH-imidazol-5-yllmethyl]aminolbenzoate
05 A suspension of 2 g (3.83 10-3 mol) of 2,2-
dimethyl-1,3-dioxolan-4-ylmethyl 2-[[[2-butyl-1-[(4-
carboxyphenyl)methyl]-lH-imidazol-5-yl]methyl]amino]-
benzoate in 100 ml of 1 N hydrochloric acid is stirred
at room temperature for 2 hours. The reaction mixture
is brought to pH 7 with a 5 N solution of sodium
hydroxide and then extracted with 2 times 50 ml of
butanol. The organic phase is washed with water and
evaporated under reduced pressure. The white foam
obtained is purified by chromatography on silica using
a methylene chloride/methanol mixture (90/10; v/v) as
the eluent to give 7.3 g (yield: 71%) of a white
powder.
M.p. = 123 C
The products of Examples 29, 30, 31, 71 and 218
were prepared by an analogous procedure.
Example 32:
.
2-[[[2-Butyl-l-r~4-carboxyphenyl~methyl]-lH-imidazol-
5-yllmethyl]aminolbenzoic acid
5.1 g (11.7-10-3 mol) of methyl 2-[[[2-butyl-1-
[((4-methoxycarbonyl)phenyl)methyl]-lH-imidazol-5-yl~-
methyl]amino]benzoate are dissolved in 50 ml of metha-
nol. 17.6 ml (35.2-10-3 mol) of 2 N sodium hydroxide
are added, the mixture is refluxed for 4 hours, the
methanol is then evaporated off and the residue is
solubilized in iced water. The diacid is precipitated
by the addition of 1 N hydrochloric acid until the pH
is 4. The solid obtained is filtered off, washed with
water until the washings are neutral, and dried over
'. , ~ . . ,' . '", . ' : !
'' , ' , " '; ''' ~ " ; . ', ',' ,'. . ~ . '" ` . : .
` ' , " ' , ' : " .' :' , " ' ', ' ' ., "'
, . '' . ' . ' .,. . ~.. , , . ~ . ' ~
,' , '''', ' ~ ' ' "' ~, ',' ~'' ''`
2~8~2
phosphorus pentoxide to give 3.75 g of a pale yellow
solid. This crude product is washed with hot methanol
to give 3.5 g (yield: 73.5%) of a white solid.
M.p. = 234 C
Os The products of Examples 33 to 52, 55, 66, 67,
198 to 212, 226 and 228 were prepared by an analogous
procedure.
Example 53:
Dipotassium salt of 2-[[[2-butyl-1- r (4-carboxyphenyl)-
methyll-lH-imidazol-5-yllmethyllamino~benzoic acid
203 mg (0.5-10-3 mol) of 2-[[[2-butyl-1-[(4-
` carboxyphenyl)methyl]-lH-imidazol-5-yl]methyl]amino]-
1~ benzoic acid are mixed with 10 ml of 0.1 N potassium
hydroxide ( 10-3 mol) and 20 ml of water. The mixture
is stirred until a clear solution is obtained, and
lyophilized to give 240 mg (yield: 100%) of a white
solid.
M.p. = 206 C
Example 54:
.
Methyl N- r [ 2-butyl-4-chloro-1-[(4-(methoxycarbonyl)-
phenyl)methyll-lH-imidazol-5-yllmethyll-N-(methyl-
carbonyl~-2-aminobenzoate
12.5 ml of acetic anhydride are added to a
solution of 2.5 g (5.31-10-3 mol) of methyl 2-[[[2-
butyl-4-chloro-1-[(4-(methoxycarbonyl)phenyl)methyl]-
0 lH-imidazol-5-yl]methyl]amino]benzoate in 25 ml of
pyridine and the mixture is heated at 60 C for 1.5
hours. The solution is poured into a cold 1 N solution
of hydrochloric acid. Extraction is carried out with
ethyl acetate and the organic phases are washed with a
1 N solution of hydrochloric acid and then with brine
,,~
. . . : ,, -
~J~
- 56 -
until the pH is 4. After drying over magnesium sulfate
and concentration, 3.3 g of a pale yellow oil are
obtained whish is crystallized from 100 ml of ethyl
ether to give 1.85 g (yield: 73%) of white crystals.
05 M.p. = 142 C
Example 58:
Methyl 2-r r r2-butyl-4-chloro-1-[(4-((triphenylmethyl~-
lH-tetrazol-5-yllphenyl~methyll-lH-imidazol-5-yl]-
methyl]aminolbenzoate
4.3 g (9.84 10-3 mol) of methyl 2-[[[2-butyl-
4-chloro-1-[(4-cyanophenyl)methyl]-lH-imidazol-5-yl]-
methyl]amino]benzoate are suspended in 80 ml of anhy-
drous toluene. 830 mg (12.7 lO-3 mol) of sodium azide
and 2.94 g (14.7 10-3 mol) of trimethyltin chloride are
added and the mixture is then refluxed for 48 hours.
After cooling to room temperature, 1.19 g (11.8-10-3
mol) of triethylamine and 4.11 g (14.7 10-3 mol) of
triphenylmethyl chloride are added. The mixture is
stirred at the same temperature for 4 hours, water is
then added and extraction is carried out with ethyl
acetate. The residue obtained after washing, drying
and evaporation is purified by chromatography using a
toluene/ethyl acetate mixture (9/1; v/v) as the eluent
to give 5.6 g (yield: 79%) of a colorless oil.
lH NMR (300 MHz; CDCl 3; ppm)
0.87 (t, 3H); 1.37 (m, 2H); 1.68 (m, 2H); 2.55 (t, 2H);
3.66 (s, 3H); 4.20 (d, 2H); 5.18 (s, 2H); 6.53 (t, lH);
~0 6.68 (d, lH), 6.91 (d, 2H); 7.14 - 7.40 (m, 15H);
7.69 - 7.72 (m, 2H); 7.95 (d, 2H).
The product of Example 59 and the following
product were prepared-by an analogous procedure:
~5
:'
- . : -.: . . . - :: :
2~92~
- 57 -
Example 217:
Pentyl 2-[[t2-butyl-1- r r 4-((triphenylmethyl~-lH-
tetrazol-5-yl~phenyl)methyll-lH-imidazol-5-yllmethyl]-
05 amino]benzoate
lH NMR (300 MHz; CDCl~; ppm)
0.88 (m, 6H); 1.23 - 1.39 (m, 8H); 1.65 - 1.71 (m, 2H);
2.58 (t, 2H); 4.10 (d, 2H); 4.16 (t, 2H); 5.18 (s, 2H);
6.58 (t, lH); 6.63 (d, lH); 6.94 (d, 2H); 7.02 (s, lH);
10 7.13 - 7.38 (m, 16H); 7.75 (t, lH); 7.82 (d, lH); 8.01
(d, 2H).
:
Example 60:
1~ Methyl 2-r~2-butyl-1-[(4-((((2-methylphenyl!sulfonyl)-
amino)carbonyl)phenyl)methyl1-lH-imidazol-5-yl]methyll-
amino]benzoate
0.6 g (3.49 10-3 mol) of orthotoluenesulfon-
amide, 0.67 g (3.49-10-3 mol) of 1-(3-dimethylamino-
; 20 propyl)-3-ethylcarbodiimide hydrochloride and 0.43 g
(3.49-10-3 mol) of dimethylaminopyridine are added to a
suspension of 1.47 g (3.49-10-3 mol) of methyl 2-[[[2-
`~ butyl-1-~(4-carboxyphenyl)methyl]-lH-imidazol-5-yl]-
methyl]amino]benzoate in 50 ml of dichloromethane.
After stirring for 20 hours at room temperature, the
-~ solvent is evaporated off under reduced pressure. The
residue obtained is purified by chromatography on
silica using a toluene/isopropanol mixture (80/20; v/v)
; as the eluent to give 1.6 g (yield: 80%) of a white
solid.
M.p. = 135 C
The products of Examples 61, 64, 187 to 194 and
227 and the following products were prepared by an
~; analogous procedure:
;:
'`
,. ~ . . ,
.. ..
. , : ~, ~.,,
2~92~2
- 58 -
Example 62:
Phenylmethyl 2-r[[2-butyl-1-~(4-((2,2-dimethyl-1,3-
dioxolan-4-ylmethoxy)carbonyl)phenyl)methyll-lH-imi-
o~ dazol-5-yllmethyl~amino]benzoate
Yellowish oil
H NMR (300 MHz; CDCl3; ppm)
0.88 (t, 3H); 1.34 (m, 2H); 1.37 (s, 3H); 1.44 (s, 3H);
1.70 (m, 2H); 2.56 (t, 2H); 3.83 (m, 1~); 4.10 (m, lH);
4.19 (d, 2H); 4.32 (m, 2H); 4.41 (m, lH); 5.18 (s, 2H);
5.22 (s, 2H); 6.64 (m, 2H); 6.91 (d, 2H); 7.05 (s, lH);
7.28 - 7.41 (m, 6H); 7.7 (t, lH); 7.92 (m, 3H).
Example 63:
1~
2-(Morpholin-1-yl)ethyl 2-[[[2-butyl-1-[(4-((2-(m~rpho-
lin-1-yl)ethoxy)carbonyl)phenyl)methyll-lH-imidazol-5-
yllmethyl]aminolbenzoate
Colorless oil
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.34 (m, 2H); 1.69 (m, 2H); 2.56 (m,
lOH); 2.73 (m, 4H); 3.71 (m, 8H); 4.19 (d, 2H); 4.32
(t, 2H); 4.44 (t, 2H); 5.19 (s, 2H); 6.64 (q, 2H); 6.95
(d, 2H); 7.04 (s, lH); 7.31 (m, lH); 7.70 (t, lH); 7.82
(d, lH); 7.92 (d, 2H).
:
Example 65:
2,2-Dimethyl-1.3-dioxolan-4-ylmethyl 2-[[[2-butyl-1-
0 r ~4-(2.2-dimethyl-1,3-dioxolan-4-ylmethoxycarbonyl~-
phenyl)methyl]-lH-imidazol-5-yllmethyl]aminolbenzoate
H NMR (300 MHz; CDCl3; ppm)
0.88 (t, 3H); 1.29 (m, 2H); 1.38 (s, 6H); 1.41 (s, 6H);
; 1.69 (m, 2H); 2.56 (t, 2H); 3.85 (m, 2H); 4.10 - 4.25
.. - i
(m, 6H); 4.35 - 4.47 (m, 4H); 5.19 (s, 2H); ~.61 (m,
,~
:, :. : . ~ : : . .:
,: .: ; . ~. . :: , .
,., : ,: ~:, :: :.:: -
~2~
2H); 6.95 (d, 2H); 7.04 (s, lH); 7.34 (m, lH); 7.65 (t,
lH); 7.86 (d, lH); 7.95 (d, 2H).
Example 68:
0:,
f(Diethylamino)carbonyllmethyl 2-r[~2-butyl-1-[(4-
((((diethylamino)carbonyl)methoxy)carbonyl)phenyl)-
methyl1-1H-imidazol-5-yl]methyl]amino1benzoate
1.09 g (10.8-10-3 mol) of triethylamine, 147 mg
(10-~ mol) of sodium iodide and 1.46 g (9.8-10-3 mol)
of N,N-diethylchloroacetamide are added to a suspension
of 2 g (4.9-10-3 mol) of 2-[[[2-butyl-1-[(4-carboxy-
phenyl)methyl]-lH-imidazol-5-yl]methyl]amino]benzoic
acid in 5 ml of dimethylformamide. The mixture is
1~ heated at 90 C for 2 hours. After cooling, water is
added and extraction is carried out with ethyl acetate.
The organic phases are washed with water, dried over
magnesium sulfate and concentrated. The crude product
obtained is purified by chromatography on silica using
a toluene/isopropyl alcohol mixture (9/1; v/v) as the
; eluent. After evaporation, 1.1 g (yield: 35%) of the
expected product are obtained.
M.p. = 55 C
The products of Examples 180 to 183 and the
2~ following products were prepared by an analogous pro-
cedure~
, .
Example 69: .
, .
(((l,1-Dimethylethyllcarbonyl)oxy)methyl 2-[[[2-butyl-
(4-((r(fl,1-dimethylethyl ! carbonyl)oxy)methoxyl-
. carbonyl)phenyl)methyll-lH-imidazol-5-yl]methyllamino~-
benzoate
Yellow oil
3~ lH NMR (300 MHz; CDCl~; ppm)
-
,,. "
- 50 ~ 2~
0.88 (t, 3H); 1.21 (s, ~H); 1.22 (s, 9H); 1.37 (m, 2H);
1.70 (m, 2H); 2.56 (t, 2H); 4.19 (d, 2H); 5.19 (s, 2H);
5.88 (s, 2H); 5.98 (s, 2H); 6.64 (m, 2H); 6.95 (d, 2H);
7.05 (s, lH); 7.35 (t, lH); 7.60 (t, lH); 7.86 (d, lH);
OS 7.95 (d, 2H).
Example 70:
(r4-Methylpiperazin-1-yllcarbonyl)methyl 2-~[[2-butyl-
1-[(4-((~(4-methylpiperazin-1-yllcarbonyllmethoxy)-
carbonyl)phenyl)methyl~-lH-imida201-5-yl~methyllamino]-
benzoate
lH NMR (300 MHz; CDCl3; ppm)
0.87 (t, 3H); 1.26 (m, 2H); 1.70 (m, 2H); 2.33 (s, 6H);
15 2.43 (m, 8H); 2.54 (t, 2H); 3.46 (m, 4H); 3.63 (m, 4H);
4.29 (d, 2H); 4.86 (s, 2H); 4.95 (s, 2H); 5.18 (s, 2H);
6.89 (d, 2H); 7.11 (s, lH); 7.39 (d, lH); 7.51 (s, lH);
7.82 (t, lH); 7.96 (d, 2H); 8.06 (d, lH).
Example 184:
r 2- r r r 2-Butyl-l- r ( 4-(~henylmethoxycarbonyl)phenyll-
,., methyll-lH-imidazol-5-yllmethyl]amino~phenylcarbonyl-
oxy]methyl butanoate
; 25 lH NMR (30~ MHz; CDCl3; ppm)
- 0.87 (m, 6H); 1.31 (m, 2H); 1.67 (m, 4H); 2.33 (t, 2H);
.- 2.59 (t, 2H); 4.19 (d, 2H); 5.18 (s, 2H); 5.35 (s, 2H);
5.88 (s, 2H); 6.59 (m, 2H); 6.90 (d, 2H); 7.04 (s, lH);
7.30 - 7.50 (m, 6H); 7.59 (t, lH); 7.82 - 7.96 (m, 3H).
~ 30
~ Example 185:
:
~, ~(Propylcarbonyl)oxy)methyl 2-r[~2-butyl-1-r(4-(r~pro-
pylcarbonyl)oxy)methoxy~carbonyl)phenyllmethyl~-lH-
imidazol-5-yllmethyllaminolbenzoate
.
`:
,. . . . . ..
-
~:, : ::. ..
: ~ . , .:
.
-t~l- 2~28~2
lH NMR (300 MHz; CDCl~; ppm)
0.93 (m, 9H); 1.34 (m, 2H); 1.63 (m, 6H); 2.36 (m, 4H);
2.56 (t, 2H); 4.19 (d, 2H); 5.18 (s, 2H); 5.88 (s, 2H);
5.96 (s, 2H); 6.61 (m, 2H); 6.92 (d, 2H); 7.04 (s, lH);
~J5 7.35 (m, lH); 7.58 ~t, lH); 7.86 (m, lH); 7.95 (d, 2H).
Example 186:
Ethyl 2- r ~ ~ 2-[[~2-butyl-1-r(4-(methox~carbonyl)phenyl)-
methyll-lH-imidazol-5-yllmethyl]aminolphenyllcarbonyl-
oxy]acetate
lH NMR (300 MHz; CDCl3; ppm)
0.85 (t, 3H); 1.29 (t, 3H); 1.36 (m, 2H); 1.69 (m, 2H);
2.56 (t, 2H); 3.91 (s, 3H); 4.17 (d, 2H); 4.26 (m, 2H);
4.71 (s, 2H); 5.17 (s, 2H); 6.65 (m, 2H); 6.94 (d, 2H~;
7.04 (s, lH); 7.33 (m, lH); 7.53 (t, lH); 7.95 (m, 3H).
"~
20 ((4-Methylpi~erazin-l-yl)carbonyl)methyl 2-[ r r2-butyl- .
l-r(4-((((4-methylpiperazin-1-yl)carbonyl)methoxy)-
carbonyl)phenyl!methyl]-lH-imidazol-5-yllmethyl]amino~-
4-nitrobenzoate trihydrochloride
~;~ 1;4 g (1.9-10-3 mol) of ((4-methylpiperazin-1-
- 25 yl)carbonyl)methyl 2-[[[2-butyl-1-[(4-((((4-methylpipe-
razin-1-yl)carbonyl)methoxy)carbonyl)phenyl)methyl]-lH-
imidazol-5-yl]methyl]amino]-4-nitrobenzoate are dissol-
ved in a mixture of 25 ml of ethyl acetate and 10 ml of
methylene chloride. An excess of ethyl ether saturated
with gaseous hydrogen chloride is added. A yellow gum
precipitates. After decantation, this is washed with
ethyl ether and dried to give 1.4 g (yield: 87%) of a
` yellow powder.
M.p. = 194 C
The product of Example 213 was prepared by an
- ,: . . .
. , :. . - :
,. ~
, . . ...
- 62 - 2~
analogous procedure.
Example 73:
~5 2-(Morpholin-l-yllethyl 2-[ r r2-butyl-l-r (4-((2-morpho-
lin-l-yl)ethoxy)carbonyl)phenyl)methyll-lH-imidazol-5-
vllmethyllamino]benzoate trioxalate
A solution of 0.302 g (3.36-10-3 mol) of oxalic
acid in a mixture of 1 ml of methanol and 5 ml of ethyl
iO acetate is added at room temperature to a solution of
0.71 g (1.12-10-3 mol) of 2-(morpholin-1-yl)ethyl 2-
[[[2-butyl-1-[(4-((2-morpholin-1-yl)ethoxy)carbonyl)-
phenyl)methyl]-lH-imidazol-5-yl]methyl]amino]benzoate
in 15 ml of ethyl acetate. The reaction mixture is
1~ stirred for 1 hour and the precipitate formed is fil-
tered off and dried under vacuum. The solid obtained
is dissolved in 20 ml of water and lyophilized to give
0.7 g (yield: 69%) of a yellowish foam.
, M.p. = 102 C
....
, Example 214:
, Pentyl 2-r r r2-butyl-1-[ ~4-(pentoxycarbonyl)phenyl)-
,, methyll-lH-imidazol-5-yllmethyllamino]benzoate
!,) 2, 650 mg (0.052 mol) of 4-dimethylaminopyridine,
1 g (0.052 mol) of 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride and 458 mg tO.052 mol) of n-
pentanol are added to a suspension of 1.07 g tO.0026
; mol) of 2-[[[2-butyl-1-[(4-carboxyphenyl)methyl]-lH-
imidazol-5-yl]methyl]amino]benzoic acid in 25 ml of
dichloromethane. The reaction mixture is stirred at
room temperature for 24 h and then concentrated under
reduced pressure. The residue is purified by flash
chromatography on silica using a methylcyclohexane/
3, acetone mixture (85/15; v/v) as the eluent to give
.; , ;. ::
;., - : .
2 ~ 9 ~ ~ 5 ~
- 63 -
1.2 g of a yellowish oil (yield: 83%).
lH NMR (300 MHz; CDCl3; ppm)
0.92 (m, 9H); 1.37 (m, lOH); 1.67 (m, 6H); 2.55 (t,
2H); 4.18 (m, 4H); 4.29 (t, 2H); 5.19 (s, 2H); 6.61 (q,
05 2H); 6.93 (d, 2H); 7.04 (s, lH); 7.30 (m, lH); 7.83 (t,
lH); 7.73 - 7.93 (m, 3H).
Example 216
<
- lO Methyl 4-r[2-butyl-5-~((2-(((3-(dimethylamino)propyl!-
amino~carbonyl~phenyl~amino)methyl]-lH-imidazol-l-yl]-
methyl~benzoate fumarate
0.96 g (1.9-10-3 mol) of methyl 4-[[2-butyl-5-
[((2-(((3-(dimethylamino)propyl)amino)carbonyl)phenyl)-
amino)methyl]-lH-imidazol-l-yl]methyl]benzoate is dis-
solved in 30 ml of ethyl acetate. The solution is
heated to 50 C and a solution of 0.214 g (1.85 10-3
mol) of fumaric acid in 4 ml of methanol is added.
After cooling to 15 C over 1 hour, the precipitate
.. i
;; 20 obtained is filtered off. After drying, 1 g (yield:
;~ 87~) of the expected product is obtained.
- M.p. = 164nC
;,
A number of compounds according to the inven-
tion have been collated in Tables I to VII below. The
1" J
symbols used in these Tables have the following mean-
ings:
~i Et = -C2H5
~` 30 n-Pr = -CH2-CH2-CH3
i-Pr = -CH(CH3)2
c-Pr = cyclopropyl
n Bu CH2 CH2 CH2-CH3
s-Bu = -CH(C~3)-CH~-CH3
i-Bu = -CH2-CH(CH3)2
- : : . . ~ .~ .
,- , . , :
. . :;. . : : , ~ . . ,. -
. .
.. .. . . . .
- 64 -
t-Bu = -C(CH3)3
n-Pen~ = -(CH2)4~C-~3
i-Pent = -cH2-cH2-cH(c~)2
c-Pent = cyclopen~yl
05 n-Hex = ~(CH2)s~CH3
c-Hex = cyclohexyl
n-Hep = -(CH2)6-CH3
n-Dec = -(CH2)s~CH3
n-Cet = -(CH2)15~C~3
Mcs = -CH2-CH2-O-CH3
Deae = -cH2-cH2-~(c2Hc)2
Gl = -CH2-CH(OH)-CH2OH
~.'
. .
~ 1~ / O
;, Ig = / 2 ~ ~ CH~
CH3
';`
~' Ph = phenyl
; Bn = benzyl
` Eph = - CH2-CH
~' .
~` N--N
TT = ~ ~ H
,~
.~, . . : ;.: :. - . :
: ~ ;:' :,. . . ,:.;.... ..
. :, : . :::
cq ~
-- 65 --
05 TTT =~
_.
'`'
.~, r
MOE = CH2- CH2- N O
~:,
,,,
~NAE: = --CHr CH~--NH--CC~
, .,
~" PZ = CH2--CO--N N--CH3
'1 /
~! 20
.
, .,
i ,~,
` '1
:: : PhSA = --CO--NH--SO"~
:`i
TSA = --CO--NH--SO
30H3C
::
OCSA = --CO--NH- SO
35 Cl
,. : .:. ~ ,
. : . : ,. ~ : : . ...
: : : ~ .
- ~6 - 2~28~2
MCSA = - CO-NH-SO2 ~
05 Cl
PCSA = - CO- NH- SO2~CI
,
-..,
:-, 10
PASA =--C~-- NH--SO2~ OCH3
, .
. 19 OASA = --CO--NH--502
;I N3
;`'
;~ MESA = -CO-NH-SO2-CH3
20 AAE = -CH2-CO-N(CH2-CH3)2
AAP = -CH2-CO-N(CH2-CH2-CH3)2
AAHE = -CH2-CO-N(CH2-CH2OH)2
AAMHE = -CH2-CO-N(CH3)(CH2-CH2OH)
APE = -CH(CH3)-CO-N(CH2-CH3)2
i~-ij 25 W = -CH2-C2-
~: X = -CH(CH3)-CO2-
,
Y = -CH2-O-CO-
Z = -CH(CH3)-O-CO-
Gly = -NH-CH2-CO-
L-Val = -NH-CH[CH(CH3)2]-CO- (L)
.. , , . - . . . ::: . . , ~, .: ; . .. , . . -
~2~
-- 57 --
TABLE A
..;,~
R~
05 ~
--~ N ~ ~ :
H
R' ~ 5
;~ Prep R', ~ R', R~s R M.p.( C)
:~ 15 2 n-Pr Cl H CH3 89
3 n-Pr H H CH3 72
4 n-Bu CF3 H CH3 S9
S n-Bu H H H 148
6 n-Bu H H Bn
9 n-Bu Cl H t-Bu 54
n-Bll Cl Cl CH3 112
11 n-Bll l H CH3 82
- 12 n-Bu H H t-Bu
31 n-Bll C l H Et 60
32 n-Bu H H Et
33 n-Bu Cl H H 126
34 n-Bu II H n-Cet 56
3; n-Bu H H n-Pent
36 n-Bu H H n-Bu
2 5 37 n-Bu H H i-Bu
38 n-Bu H H CH2-c-Pr
::. 39 n-Bu H H i-Pent
ll-Bu Cl H Bn
-~ 62 n-Bll S-CH3 H CH3 72-74
~:
`~ 30 _ _ _
,.
. .
: - , . . . ..
,. . .,; . ... . . ,. ,, ~, , . : , ,
- 68 - 20928~2
~,
:
TABLE B
:
.
.. ...
,,. n2
, 05
N ~
¦ OH
;'i 10 ~/
~,` R ~ ~ ~ R'5
. O '
,.,~
,", . .... _
., l, Prep R'~ ¦R', R~5 R M.p.( C)
~ ._
7 n-BII H H CH3 144
13 n-Bll C~3 H CH3 113
14 n-Bll Cl Cl CH3 108
:, 15 n-Pr Cl H CH3 120
16 n-Bll ~1 H t-Bu 163
- 20 17 n-Bll H H Bn 111
18 n-BIl I H CH3 150
19 n-Bu Cl H t-Bu 174
n-Bu Cl H CH3 94
21 n-Pr H H CH3 135
41 - n-Bu S-CH3 H CH3 154
42 n-Bu H H n-Pent 137
:` 25 43 n-Bu H H Et 140
:: 44 n-Bll H H n-Bu 140
. 45 n-Bu H H n~Cet 7S
46 n-Bll 11 H i-Bu 144
~: 47 n-Bu 1 1 HCH2-c-Pr 100
48 n-Bll H H i-Pent 170
49 n-Bll Cl H Bn 127
:
:'
~92~2
-- 59 --
TABLE c
05 R'2
: N /
R 1 --~N
` 10 ~ Cl
R ~ ~\ R~s
, O
Prep ¦R~l ¦ R', I R~s ¦ R M.p.( C)
.
8- n-Bu H H CH3 158
2' n-Pr Cl H CH3 128
23 n-Bu H H Bn 160
21 n-Bu H H t-Bu 150-191
n-Bu Cl Cl CH3 70
26 n-Bu I H CH3 140
27- n-Bu Cl H t-Bu 133
28- n-Bu Cl H CH3 120
29- n-Pr H H CH3 172
n-Bu CF1 H CH3
Sl- n-BIl S-C~3 H CH3 11S
~i' 53- n-Bu H H n-Pent 130
$4- n-Bu H H Et 130
SS- n-Bu H H n-Bu 130
56- n-Bu H H n-Cet 135
57- n-Bu H H i-Bu 148
58- n-Bu H H CH.-c-Pr 150
S9- n-Bu H H i-Pent 135
61 n-Bu Cl H Bn
Note: * hydrochlorides --
- ?0 - 2 ~
, ~
TABLE D
NH o
~X~
Ra
,
~,
,, 10
. :
Prep ¦ R, ¦Y~ ¦ R~, ¦ M.p.( C)
1~ 64 H O AAP 64
6i H O CH(CH3)(CO)Et
; 66 H O W-Et
67 H O W-n-Pent
68 H O CH,-c-Pr
69 1-1 CH. CO-Et 53
H O Desle
72 H O APE 134
73 H O AAHE 107
74 H O AAMHE 103
H O Z-t-Bu 80
76 H O Z-cH(Et)2
77 H O Z-c-Pent .
78 H O Z-c-He~
. 79 H O Y-n-Pent
H O Z-n-Pent
81 H O Z-CH.-c-He:c
82 H O i!-CH.-c-Pent
., 83 H O Y-t-Bu
84 ~1 .~ H(CH~)3-N(CH3)2 76
~' 85 H .~H AAE 62
86 H ~,'HCH(iPr)-CO2Et
87 6-CH3 O n-Pent
88 6-CI O n-Pent
~2~
-- 71 --
'rABLE I
05 R2
R, ~
~ J o~5
~ ~ 6
H3C ~ `~ ~ R5 --CH3
O
1~
E.YRl R ¦R, ~RJ R5 M.P.( C)
1 n-Bu H H H H
2 0 2 n-Bu H H 4-NO. H 144
3 n-Pr H H H H
6 n-Bu Cl H 3,5-diCl H
; 7 n-Bu Cl H 3-CH, H
8 n-Bu Cl C~I1 H H
9 n-Bu Cl H 3,4,S-tri OCH, H
10 n-Bu Cl H H H
13 n-Pr Cl H H H 108
14 n-Bu Cl H S-CI H 90
:: . lS n-Bu Cl H 4-Cl H 116
17 n-Bu Cl H 4-NO~ H 136
18 n-Bu Cl H S-CH; H
i 19 n-Bu I H H H
20 n-Bu CF, H H H
21 n-Bu Cl Il H Cl 140
54 n-Bu Cl COCHl H H 142
75n-BII SC~I3 H H H
116n-Pr H H 4-NO. H
225n-Bu H H 4-N3 H 132
Note: * double melting point: 87 C, then 97 C
,~
- -, . . . . ~ - . . .
- 72 - 2~2~
:
TABLE I I
::
:' 05 R~
~ / R
R, --N~l R4
: ~J O ~ 5
HO
O
1~ EY R, ¦ R ¦ R, ¦ R~ Rs¦ M.p.~ C) ¦
32 n-Bll H ~ 1~ H H 234
n-BIl ~ 4-NO. H 250
36 n-Pr H I I H H 249
37 n-Bll Cl 1-1 3-CH, H 115
3~ n-Bll Cl Cll, H H 147
39 n-Bll Cl H 3,;-diCl H 220
n-Bll Cl 11 3,4,5-tl-i OCH, H 212
41 n-Btl Cl H H Cl 244
42 n Pr Cl H H H 246
; 43 n-Bn CF, 11 H H 262
: 44 n-Bll I 11 H H 225
n-Bu Cl H ;-CH, H 232
46 n-Btl Cl H 4-NO. H 260
. ~ 48 n-Btl Cl H 4-Cl H 247
.. 49 n-Btl Cl H S-CI H 248
n-Btl Cl H H H 235
. 55 n-Btl Cl CO CIIl H H 230
: 198 n-Bu SCH3 H H H 207
199 n- Bn H I-l 6-CH3 H 225
200 n-Btl 11 11 6-Cl H 259
212 " p~- H ~l 4-NO. H 281
216 n-B~ 11 H 4-N3 H215(dec)
~ .
`~;
.. . . .. . ....
2~2~
-- 73 --
TABLE I I I
05 R2
~ ~NH~4
,~ o~5
OR'
RO ~W
.; 11
O
E.Y ¦ R, ¦ R I R n~ M.p.( C)
4 n-B~l l~ l Bn
i Il-Bll H l t-Bu Bn
22 n-Bll Cl ! t-Bu CH, 102
23 n-Bll Cl l ~I CH, 181
2~ n-Bll I~ CH, 85
n-Bll ~1 I-I Bn 90
26 n-Bll H ¦ H Ig 92
27 n-Bll H Ig H 202
: 28 n-Bll H H Gl 123
29 n-Bu H Cl H 134
S3 I~Bu H 1~ K 206
~; 62 n-Bll H Ig Bn
; 2 5 63 n-Bu H MO E ~IO E
64 ll-Bu H NAE ~AE 84
n-Bll H Ig Ig
63 n-Bll H AA E ~AE 55
~ 69 n-Bll H Y-t-Bu Y-t-Bu
:~- 70 n-Bll- H Pz Pz
71 n-Bll H Gl Gl 60
73''n-Bll H MOE I~IOE 102
::
. .
.`
:;~
- ~ . " . ". .,, .; , , .~.. '; . - ,. - . .
-- 74 --
~28~2
TABLE I I I ( continuation l ~
0 5 I I l _
Ex IR, I R ~ R R' M.p.( C)
74 n-Bu Cl Bn ~ n-Pent
76 n-Bu H CH~ AAE 81
77 n-Bu H CH3 AAP
78 n-Bu H Bn AAP
79 n-Bu H Bn AAE
n-Bu H Bn APE
81 n-Bu H Bn AAHE
82 n-Bu H Bn AAMHE
84 n-Bu H Bn W-Et
n-Bu H Bn Z-CH-Et2
86 n-Bu H Bn Z-c-Pent
n-Bu H BnZ-CH~-c-Pent
91 n-Bu H BnZ-c Hex
92 n-Bu I I BnZ-t-Bu
93 n-Bu H BnY-t-Bu .
94 n-Bu H BnY-n-Pent
n-Bu H BnDeae
96 n-Bu H BnCH(CH3)-n-Bu
97 n-Bu H BnCH(CH~)-CO-E
2 0 98 n-Bu H CH3CH.-~:O-Et 100
: .~ 99 n-Bu H BnCH2-CO-Et
100 n-Bu II Bn X-Et
101 n-Bu H Bn~V-n-Pent _
102 n-Bu H Bn EPh
103 - n-Bu H Bn Ph
104 n-Bu H Bn Mcs
:~ 105 n-Bu H Bnn-Dec
106 n-Bu 11 Bnn-Hep
107 n-Bu 1-1 Bni-Pent
108 n-Bu H Bn . i-Pr
109 n-Bu H Bn CH~-c-Pr
: ~ 110 n-Bu H Bn i-Bu
111 n-BIl H Bn n-Cet
11~ n-Bu I-I Bn n-Bu
113 n-BIl II Et Et
114 n-BIl }1 Cl13 n-Pent
. l lS n-PI I I Bn n-Pent
. ~ 11~ n-Bu lI Bn Z-n-Pent
_ n-Bll 11 Bn t-Bu
; 35
:::~ - : :. , : , ,:
,. " .,
::.: . . , .
~9~8~2
-- 75 --
TABLE III ( continuation 2 )
0 5
Ex Rl R, ¦ R R' M.p.(
120n-Bu H Bn Et
121n-Bu H CH3 Z-n-Pent
122n-Bu H Bn n-Pent
123n-Bu H Bn Z-CH2-c-Hex
124n-Bu H n-Pent Bn
125n-Bu H CH3 Bn
126 n-Bu H Et Bn . -
127 n-Bu H n-Bu Bn
128 n-Bu H n-Cet Bn
129 n-Bu H i- Bu Bn
130 n-Bu H -CH.-c-Pr Bn
131 n-Bu H i-Pcnt Bn
134 n-Bu H H AAP 140
135 n-Bu H H AAE 168
136 n-Bu H H APE 13S
137n-Bll l~ H AAHE 108
138 n-Bu H 1~ AAMHE 110
139 n-Bu H H Z-CH-Et2 170
140 n-Bu H H Z-c-Pent 170
141 n-Bu II H W-Et 15S
144n-:l~u H H Z-CH,-c-Pent 154
145 n-Bu H H Z-c-Hex 60
146n-l~ll H H Z-t-Bu 90
147n- Bu H H Y-t-Bu 160
. 148 n-Bu H H Y-n-Pent 140
149 n-Bu H H Y-n-Pr 162
150 n-Bu H H Deae 68
;:: 25 151 n-Bu H H CH(CH3)-n-Bu 74
~, 152 n-Bu II H CH (CH3)-CO-Et 80
.~ 153 n-Bu H H X-Et 164
154 n-Bu 11 H ~V-n-Pent 157
155n-Bll H H CH.-CO-Et 144
.: 156 n-Bu II H EPh 128
157 n-Bu H 1-l Ph 231
158n-Bll H H Mcs 78
lS9 n-Bu ll n-Dec S0
:~
~ . , . , ~ . . .
.: , - :: . : : . .: , .,.:., . . : . , :;
: ~, : , ~
:~ . : ; .: . , :.
~2~ g~
-- 76 --
TABLE I I I ( end )
05
l R ~ - R' M.p.( C)
160 n-Bu H H n-Hep 96
161 n-Bu H H i-Pent 164
162 n-Bu H H i-Pr l72
163 n-Bu H H CH2-c-Pr 171
164 n-Bu H H i-Bu 163
165 n-Bu H H n-Cet 82
166 n-Bu H H n-Bu lSl
167 n-Pr H H n-Pent 177
168 n-Bu H H Z-n-Pent 143
169 n-Bu H H Et 173
170 n-Bu H H n-Pent 161
171 n-Bu H H Z-CH,-c-Hex 114
172 n-Bu H n-Pent k 202
173 n-Bu H CH3 H 188
171 n-Bu H Et H 201
175 n-Bu H n-Bu H 194
176 n-Bu H n-Cet H 152
177 n-Bu H i-Bu H 190
178 n-Bu H CH,-c-Pr H 198
179 n-Bu H i-Pent H 197
181 n-Bu H AAP AAP 97
182- n-Bu H Pz Pz 250-260
184 n-Bu H Bn Y-n-Pr
18; n-Bu H Y-n-Pr Y-n-Pr
186 n-Bu H CH3 W-Et
196 n-Bu H Bn H 17S
213-- n-Bu H H Deae 206
2s214 n-Bu II n-Pent n-Pent
~4 n-Bu Cl H n-Pent 145
_
Notes: *: 3 HCI
;: **: 3 HO.C-CO~H
". ***: 2HCI
~ 30
:
3s
f
:- : . : ., ~ . -,, ~ . ~ .. . : . . .
2~2~2
-- 77 --
TABLE IV
05 N~
R ~ ~ ~ NH~3
`
~ R"'
R~ ~ ~/
Ex R~ R,I R~ R~ ¦ M.p.( C)
n-Bu ClI TT CO CH3 185
31 n-Bu ClI CO.CH3 ~T 182
Sl n-Bu Cl TT CO2H 158
j2 n-Bu ClCO,H TT 200
56 n-Bu Cl C~ Co2CH3 126
57 n-Bu ClCO,CH3 CN
j8 n-Bu Cl TTT CO~CH3
59 n-Bu ClCO,CH3 TTT 130
n-Bu H TSA CO2CH3 135
61 n-Bu Cl TSA CO CH3 244
66 n-Bu Cl TSA CO H 234
67 n-B~ H TSA CO2H 190
88 n-Bu HCO,CH3 CONH-AAE 42
89 n-BIl HCO;CH3 CONHOCH3 146
132 n-Bu H 4-CN CO2-n-Pent
142 n-Bu H CO.H CO-L,Val-OEt 110
143 n-Bu H CO2H . CO-Gly-OEt 140
187 n-Bu H TSA CO2-Y-n-Pr 228
188 n-Bu H OCSA CO2CH3 125
189 n-Bu H MCSA Co2CH3 145
190 n-Bu H PCSA CO2CH3 220
Il-~U H PllSA CO2CH3 120
192 n-Bu H PASA CO2CH3 228
193 n-Bu H MESA CO2CH3 120
194 n-Bu H OCSA CO2-n-Pent 259
-I
` .. ' . ; ,. ~: - ` . - . . : :, . : . ~.; ;. ':
~ ~ ~ 2 ~ r~ 2
- 7~ -
TABLE IV ( end )
~5
~ ~ ' n. ¦ R" M.p.( C)
201 n-Bll H ¦ .~ICSA CO2H 235
202 n-Bu I I PCSA CO,H 215
; 203 n-Bll H PllSA CO2H 203
204 n-Bll H PASA CO2H 193
205 n-Bll H .~lESA CO2H . 238
: 206 n-BIl H CO.I-ICONH(CH )3N(CH3)2 111
207 n-Bu H CO;H CO~-AAE 92
208 n-Bll H CO;H CONnH-O-CH3 211
209- n-BIl 11 CO;H CO~nH2 196
210 n-Bll H CO;H CONnI(n-Bu) 183
211 n-Bu H OCSA CO2H 198
215 n-Bu 1~ CO.CH3CONnH(CH2)3N(CH3)2
2I6'' n-Bu H CO;CH3CONlH(CH.)3N(CH3)2 164
217 n-Bll H TTT CO2-n Pent
2I8~ n-Bll H TT CO2-n-Pent 204
219 n-Bll 11 CO.C1-13 CONH2 186
: 220 n- Bu 11 CO; C1~3 CONH(n-Bu) 125
221 n-Bll 11 CO;-Bn CO-I,-Val-OEt
222 n-BIl H CO;-Bn CO-Gly-OEt 107
: 227 n-Bu H OASA CO CH3 150(dec)
22~ n-Bu H OASA C~2H 150(dec)
.; .. _ _
. .
;: ~ote :~ HCl~ fum~l.lte
;
2 ~
-- 79 --
TABLE V
R2
N ~ \~=(
R Jl \\
~ I \ N / N ~,~
'-; 10
` ~ O OR
~: 0~
, 1
` OR
~' 15
~'
-
'3
.:
PrepR, R R M.p.( C)
11 n-Bll Cl CH, CH CH, 136
12 n-Bu H CH, CH CH, 86
33 n-Bu H H H 28û
: ~ 25 3J n-Bu ~ 11 268
;:
:~ `
:`
~,
.~ : :: ` , , -:, ~ : , . , : ` - :, . . . .
,:, ` .. : .: : .. , :, .:` :: . , ~` -::`: ;`
:.. : : :: : : :: - : . : : ` ` : . : . .
2~2~2
-- 80 --
TABLE VI
05 R2
R, ~ , N
OR
.
Prep R, i R~ ¦ R ¦ R' ] ~.p.( C)
: 20 16 n-Bu Cl CH, CH,
47 n-Bu Cl H H 221
~,
:
:`!
.
i'''
.
~ 30
,
: 35
- 81 - 2~928~2
TABLE VI I
05 '
n Bu ~~ R4
`' 10
RO 1~ ~ CR'
o
E.Y R ¦ R' ¦ R~ M.p.( C)
_
72- Pz Pz 4-N O. 194
83 CH3 n-Pent 6-CI
87 CH3 n-Pcllt 6-CH3
117 t-Bu CH3 4-NO.
133 t-Bu n-Pellt 4-NO;
180 AAE AAE 4-NO; 158
183 Y-t-Bu Y-t-Bu 4-NO2 83
195 H CH3 4-NO2 234
197 H n-Pent 4-NO2 161
~3 H n-Pent 6-CH3 153
Note: * 31~CI
.~
;~
`'
~92g~2
- 82 -
The products according to the invention are
inhibitors of the effects of angiotensin II.
The activity of the compounds according to the
invention as angiotensin II vascular receptor anta-
05 gonists was evaluated by their efficacy in antagonizingthe contractile response induced by angiotensin II in
isolated rabbit aorta rings. The rings are suspended
in a bath of Krebs-Henseleit maintained at 37 C and
aerated with an O2/CO2 mixture (95/5; v/v), and are
-10 then stretched to a rest tension of 2 g. After one
hour at rest, a contraction is caused with angiotensin
II (3-10-9 M) in the presence of the test product pre-
~incubated for 15 minutes. The concentration (expressed
;in nanomol) of test product which produces a 50% inhi-
bition of the contractile response (IC50) is calculated
from the concentration-response curve. The results
obtained with a number of compounds according to the
invention are collated in Table VIII.
The products according to the invention are
useful in therapeutics in the treatment or prevention
of arterial hypertension, glaucoma, circulatory dis-
orders, restenosis due to angioplasty, developments of
atheromatous or fibrinoproliferative lesions, nephro-
pathy and retinopathy of diabetic origin, infarctus and
angor and for improvement of the cognitive function.
According to the invention, a therapeutic com-
position is recommended which contains at least one
'compound of formula I or one of its addition salts in a
therapeutically effective amount in association with a
physiologically acceptable excipient.
It is also recommended to use the compounds of
formula I or one of their addition salts as angiotensin
iII antagonists in order to obtain a drug for the pre-
vention or cure of arterial hypertension, circulatory
disorders and glaucoma.
. :
,:
~v~2$~2
-- 83 --
TABLE VI I I
05
_
Ex ICso (~10-9 ~ _ Ex ICso (xlO-9
26 100 156 82
28 80 157 54
32 3.6 158 75
33 7,1 161 64
lo 34 8.4 163 50
1.2 164 40
36 7 166 15
39 I06.2 168 67
57.6 170 80
41 5.1 174 80
42 ~.1 178 67
~3 6.3 180 30
44 5.3 181 80
6.7 183 60
46 lO.S 187 7
~7 71.3 195 82
48 5.3 197 5;
49 13.2 198 4.6
j.7 ?01 10
~1 10.8 202 14.7
52 40.2 203 4.4
iS 69.1 204 9.5
66 8.~ 205 5.5
67 1.3 ~09 70
68 30 210 ~4
76 - 90 211 0.8
134 35 212 46
141 10 2?6 6
1485 412 228 2
" 155 ~5.~
.~ _
:,
. .
.
J 35
~.
i
- ~ . , ` ' ' ' : ;: : i.' ` '' ' ' ' ': ~' ` `' ` :' ` ' ., ~ : :` . '
