Note: Descriptions are shown in the official language in which they were submitted.
12410~3
--1--
TITLE
Dopamine-B-hydroxylase Inhibitors
FIELD OF THE INVENTION
This invention relates to inhibitors of
dopamine-~-hydroxylase.
15BAC}~GROUND OF THE IN~tENTION
In the catecholamine biosynthetic pathway,
tyrosine is converted in three steps to norepinephrine
(NE). Intermediates are dihydroxyphenylalanine (DOPA) and
dopamine (DA). The latter is hydroxylated to norepine-
phrine by dopamine-~-hydroxylase (DBH) in the presence of
oxygen and ascorbic acid.
Inhibition of catecholamine activity has been
found to decrease hypertension. See, for example, Matta
et al., Clin. Pharm. Ther. 14, S4~ (1973), and Teresawa et
al., Japan Circ. J. 35, 339 (1971). Weinshilboum, Mayo
Clin. Proc. 55, 39 (1980), reviews compounds which inhibit
catecholamine activity by interfering with adrenergic
receptors. Alternatively, the catecholamine biosynthetic
pathway can be suppressed at any of the three steps,
resulting in decreased levels of ~E. In addition to
decreasing hypertension, inhibitors of NE synthesis are
active as diuretics, natriuretics, cardiotonics and
vasodilators. Inhibition of DBH activity can have the
added advantage of increasing levels of DA, which as
reported by Ehrreich et al., "New Antihypertensive Drugs,"
Spectrum Publishing, 1976, pp. 409-432, has been found to
, "
~ Q n 3 2-
1 have selective vasodilator activity at certain
concentrations.
DBH inhibitors have also been shown to reduce or
prevent formation of gastric ulcers in rats by Hidaka et
al., ~Catecholamine and Stress," edit. by Usdin et al,
Permagon Press, Oxford, 1976, pp. 159-165 and by Osumi et
al., Japan. J. Pharmacol. 23, 904 (1973).
Although there are many known inhibitors of DBH,
none of these agents has found clinical application
10 because of non-specific, often toxic, properties they
possess. Fusaric acid, for example, has been found to be
hepatotoxic. See, for example, Teresawa et al., Japan.
Cir. J. 35, 339 ll971) and references cited therein.
Presumably, the picolinic acid structure interacts with a
15 number of metalloproteins and enzymes in non-specific
fashion to produce observed side effects.
In U. K. specification 1,155,580 are disclosed
compounds having the formula:
SH
Rl- N N
R2 R3
wherein R2 and R3 can be H and Rl can be substituted
phenyl. The compounds are said to have analgesic,
anti-inflammatory and antipyretic properties. Gebert et
al., U.S. Patent 3,915,980, disclose such compounds
wherein Rl can be phenyl or phen (Cl 3) alkyl, as
intermediates to imidazolyl-2-thioalkanoic acid esters.
Iverson, Acta Chem. Scand. 21, 279 (1967) reports
a compound having the formula:
lZ4~003
--3--
~CE~2 ~ N ~ N
ll ~ ~
S ~
wherein R can be -CO2H or -CH2NHC6H5, but does not
report a pharmaceutical use for the compound.
SUMMARY OF THE INVENTION
The invention provides a compound selected
from the group and having the formula:
CHO
~CH2~n /~
~ Xl N N and
~ ~ N
y~
wherein
n is 0-4;
M is an organic salt of an alkali metal;
yl is -H, -OCH3, -F, -CF3 or C1_4 alkyl;
xl IS -H, -OCH3, -F, -CF3 or Cl_4 alkyl,
or any accessible combination thereof up to four
substitutents and a process for their preparation.
The process comprises, desulfurizing a basic
thioimidazole, and treating it with an organic salt
of an alkali metal so as to obtain a compound of
the formula:
12410(~3
-3a-
M
I
2~ ~
N
yl_ \~ 1 \=/
and if desired, reacting said
~ H2~n~N ~ N
Y~
with a di-substituted foramide to yield a compound
of the formula:
CHO
I
~_~H2~ 3
The invention resides in the discovery that
DBH can be inhibited by a compound having an
imidazole-2-carboxylic acid or 2-aminomethyl
imidazole moiety and a phenethylamine analogue
moiety. More particularly, the invention is
selected novel compounds having the formula:
~ CH2 ~ N ~ N
Y~ ~/
wherein
Y is -H, -OH, -OCH3, -F, -CF3 or C1_4
alkyl;
.~
lZ41003
-3b-
X is -H, -OH, -OCH3, -F, -CF3~ C1_4 alkyl~
of any accessible combination thereof up
to four substituents;
R is -CO2H or -CH2NHRl;
R1 is -H, phenyl or benzyl; and,
n is 0-4,
or a pharmaceutically acceptable acid addition salt
or hydrate thereof, provided that when R is -CO2H
or -CH2NHC6H5, X is -H and n is 1, Y is not -H.
"
12~10~3
-
1 In one preferred embodiment of the compounds of
the invention, R is -CO2H and n is 1 or 3. In a second
such preferred embodiment, R is -CH2NHR ; Y is -H or
-O~; R is -H or benzyl; and n is 1.
The invention is al~o a method of inhibiting DBH
activity in mammals which comprises administering
internally to a subject an effective amount of a compound
having the formula:
~C H 2~ J~
Y~ ' \~
wherein
Y is -H, -OH, -OCH3, -~, -CF3, Cl_4
alkyl;
X is -H, -OH, -OCH3, -F, -CF3, Cl_4
alkyl, or any accessible combination thereof up to
four substituents;
R is -CO2H or -CH2NHR ;
Rl i8 -H, phenyl or benzyl; and,
n is 0-4,
or a pharmaceutically acceptable acid addition salt or
hydrate thereof.
In the preferred method of the invention, R is
-CO2H and n is 1 or 3, or, R is -CH2NHRl, Y is -H or
-o~, R is -H or benzyl, and n is 1.
The invention includes pharmaceutical
compositions comprising the compoun,ds which are useful in
the method of the invention and a pharmaceutical carrier.
Pharmaceutically acceptable acid addit:ion salts, and
hydrates, are included within the above formulae.
1~41C3~
1 The invention is also a compound having the
formula:
CHO
~ 2
Y ~Xl ~
wherein
yl is -H, -OCH3, -F, -CF3 or Cl_4 y
xl is -H, -OCH3, -F, -CF3 or Cl_4
15 alkyl, or any accessible combination thereof up to four
substitutents.
n i~ 0-4.
This compound is converted to the 2-aminomethyl imidazole
20Of the invention by reducing the compound.
The invention is also a compound having the formula:
2 5 ~ ~n~ /~?
y~
\
wherein
yl is -H, -OCH3, -F, -CF3 or Cl_4 alkyl:
xl is -H, -OCH3, -F, -CF3 or Cl_4 alkyl,
or any accessible combination thereof up to four
35 substituents;
~,
lZ41003
--6--
1 n is 0-4; and,
~ is an organic salt of an alkali metal.
This compound is converted to the imidazole-2-carboxylic
acid of the invention by quenching with C02.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention contain a weak
metal-chelating functional group. They also contain a
phenyl moiety as do phenethylamine analogue inhibitors
such as benzy}oxyamine, benzylhydrazine, tryptamine and
10 serotonin.
The compounds of the invention can be prepared
from corresponding 2-mercapto-1-(4-methoxyaryl)imidazoles
by procedures such as those illustrated in the Examples
below. Starting mercaptoimidazoles are known (see, for
15 example, U.S. 3,915,980 and U.K. 1,155,580) or can be
prepared from corresponding benzaldehydes, which are known
and described in published references or are readily
accessible by known techniques, such a~ illustrated in
Scheme I, depicted below, wherein Xl and yl are X and
20 Y, respectively, except that w~en Y is _o~, yl is
-OCH3 and when X is -OH, Xl is -OCH3. As
illustrated, n is one, although n can be 0-4. Scheme I
illustrates reductive amination of the benzaldehydes (I)
with an amnoacetaldehyde acetal followed by reduction by,
25 for example, catalytic hydrogenation or treatment with a
reducing agent such as NaBH4, LiAlH4 or A1~3, to
provide intermediate substituted benzylamines (II). Upon
reaction with acidic thiocyanate, the intermediates II
yield starting mercaptoimidazole compounds (III) which can
30 be converted to the compounds of the invention by
procedures known in the art, such as described below and
as illustrated in the examples which follow.
12~1003
--7--
1 Scheme I
J ~ MH2CH2CH(OcH2cH3)2 ~ ~ NCH2CH(OCH2CH3)2
H2/Pd ~ yl ~NH~H2CH(OCH2CH3)2
II
. SH
H+/~CN ~ yl ~ N ~ N
. III .
The l-phenyl sub~tituted 2-mercaptoimidazole
starting compounds (n i~ O) are preferably prepared by
20 reaction of an appropriately substituted phenyl
isothiocyanate wlth an aminoacetaldehyde acetal followed
by ~trong acid c~talyzed cyclization, as illustrated in
Example 1, below.
The compoun~s wherein n i~ 2,3 or 4 are
25 preferably prepared as described in Example 4, below.
Coupling of substituted phenyl alkanoic acids as the acid
chlorides with aminoacetaldehyde acetals and subsequent
reduction provides such intermediate substituted phenyl
alkylamines.
yl in Scheme I is the same as Y except that
when Y is -OH, yl is -OCH3 deprotection of the
4-alkoxy group with, for example, BBr3 or HBr, or
nucleophilic aromatic substitution with dilute hydroxide,
provides the phenol (Y is -OH). X may be one or more
35 substituents at the 2-, 3-, 5- or 6-positions provided the
combination of substituents i8 accessible, that is, does
not result in significant instability due to steric
124~003
--8--
1 hindrance. When Xl is -OCH3, it can be deprotected as
described above for Y .
Rane ~ nickel desulfurization of the starting
mercaptoimidazoles (III) provides parent aralkylimidazoles
5 which can be treated with an organic salt of an alkali
metal to provide intermediate aralkyl substituted
2-alkaliimidazoles. The alkali substituent can be
replaced such as by quenching with disubstituted
formamides to give the 2-aldehydes, as in Example 5, or
10 with C02 to give the 2-carboxylic acid, as in Example 9.
The corresponding substituted aminomethyl
compounds (R is -CH2N~Rl wherein Rl is -~, phenyl or
benzyl) can be prepared from the 2-aldehydes by reduction
of intermediate 2-aldoximes or o-alkyl ethers of
152-aldoximes as illustrated in Example 6, or by reductive
amination with primary or secondary amines as illustrated
in Example 7.
The pharmaceutically acceptable acid addition
salts of the compounds of the inventlon are formed with
20 strong or moderately strong organic or inorganic acids by
methods known to the art. For example, the base is
reacted with an inorganic or organic acid in an aqueous
miscible solvent such as ethanol with isolation of the
salt by removing the solvent or in an aqueous immiscible
25 solvent when the acid is soluble therein, such as ethyl
ether or chloroform, with the described salt separating
directly or isolated by removing the solvent. Exemplary
of the salts which are included in this invention are
maleate, fumarate, lactate, oxalate, methanesulfonate,
3~ ethanesulfonate, benzensulfonate, tartrate, citrate,
hydrochloride, hydrobromide, sulfate, phosphate and
nitrate salts.
The compounds of the invention, because they can
be used to inhibit DBH activity, have therapeutic value as
35 diuretic, natriuretic, cardiotonic, antihypertensive and
lZ41003 9
1 vasodilator agents, as well as antiulcerogenic and
antiparkinson disease agents. Compounds of the invention
and the compounds wherein R is -CO2H or
-CH2NHC6H5, Y i8 -H, X is -H and n is 1, which
compounds are useful in the method of the invention, were
screened for in vitro DBH inhibition by a standard
procedure for assaying conversion of tyramine to
octopamine in the presence of DBH. Octopamine was assayed
following sodium periodate oxidation to p-hydroxy-
10 benzaldehyde by measuring spectrophotometric absorbance at330 nm. Results are given in Table I, below. Inhibition
is given in molar concentration of compound at which DBH
activity was halved (IC50). Melting points ~mp) are
given in C. Fusaric acid, by this test was found to
15 have an IC50 of 8x10 7.
~able r
Com~ound ~P ICSo
R Y X n
C82N~2 2~Br OH ~ 1 252-254 3.5 x 10 5
C02~-Hcl a ~ 1 129(dec) 1.1 x 10 5
CO2~ HCl OH H 1 142(dec) 9.0 x 10 5
CO2~ 1/2 ~2 ~ ~ 3 136(dec) 7.0 x 10 5
Co2~-Hcl ~c~3 8 } 132(dec) 7.5 x 10 5
C~2NHC6~5 2BBr OH ~ 1 198-200 ' 10 4
CO2~ HCl OC~3 H 3 130(dec) 9.5 x 10 5
C~ NH 2~Cl H a 1 185-187 2.4 x 10 4
C~2NHC6HS-2HC1 ~ ~ 1 20fi 1.0 x 10 4
The following procedure was used to test, for in
vivo activity, compounds which can be used to inhibit DBH
activity in mammals, including certain illustrative
compounds of the invention. The compounds wherein R is
-CO2H or -CH2NHC6H5, X is -H, Y is -H and n is 1
35 are not compounds of the invention but can be used in the
1~1003 -10-
1 method of the invention.
Male~ Okamoto-Aoki strain spontaneously
hypertensive rats, aged 16-20 weeks, were used for
testing. The afternoon before testing, the animals were
fasted and the following morning the first dose of the
test compound was administered, p.o., along with a 25
ml/kg load of normal saline. The animals were then placed
in metabolism cages, three per cage, and urine was
collected for three hours and subsequently analyzed for
10 sodium, potassium, and creatinine Indirect systolic
blood pressure and heart rate were measured via a
tail-cuff method and the animals received an identical
second dose of the test compound. Two hours after the
second dose, the systolic blood pressure and heart rate
15 were again determined. Drugs were administered as a
solution or suspension in normal saline with 0.02%
ascorbic acid.
Three rat~ weighing 270-320 g were used. Each
received two intraperitoneal injection8, in a 24 hour
20 period, of a dose volume of 5 mL and a dose concentration
of 50 mg/kg or 25 mg/kg, in 0.9% NaCl, following a 24 hour
pretreatment dose. Averaged results were as tabulated in
Table II, below. Averaged results with control animals,
three per experiment, are reported in parentheses below
25 results of test animals.
1241003
--11--
3 OD ~O
_ _ _ _
O O O 0-- g 0-- 0
o
D ~ ~ ~ O
o /~4 e _ _ _ _
10 ~ ~
C~
o
:1~ D _ _ _ _
CO _l
a ~ .
_ _
20 ~ Is r~
_ ~,~, _ ~ _
3 ~ o ~ ~ ~ o o o
.~ ~o ~ , ~ ~o ,
2!j ~ _
O ~ _ _ _ ~
I ~ r~ 0 ~~
z _ _ _ ~ -'
co ~o o~ ,, oo
7 ~ , 7
c o ~ 8 1 ' ~ 8 ~
9 11 ~ 11 U ~ O 11 U ~ 3 2
~ x ~ ~ ~ ~ c ~ ~ x ~: e ~ ~ ~ ~ e
~24~003
1 Analysis of the above-tabulated results indicates
that the compounds inhibit DB~ activity as shown by the
IC50 data and/or by their in vivo natriuretic, diuretic,
and antihypertensive and/or cardiotonic activity. For
5 example, the compound in which R is -C02H, X and Y are
-H and n is 3 showed significant in vivo activity as a
natriuretic, diuretic, antihypertensive and cardiotonic
agent; the compound in which R is -C02H, Y is -OH, X is
-R, and n is 3 showed significant diuretic activity; the
10 compound in which R is -CH2NH2, Y is -OH, X is -H, and
n is 1 showed significant antihypertensive activity; the
compound in which R is -CH2N~C6H5, Y is -OH, X is -H
and n is 1 showed significant cardiotonic activity.
Compounds having diuretic activity are known to be useful
15 as antihypertensives.
The compounds can be incorporated into convenient
dosage unit forms such as capsules, tablets or injectable
preparations. Pharmaceutical carriers whlch can be
employed can be solid or liquid. Solid carriers include,
20 among others, lactose, terra alba, sucrose, talc, gelatin,
agar, pectin, acacia, magnesium stearate, and stearic
acid. Liquid carriers include, among others, syrup,
peanut oil, olive oil and water. Similarly, the carrier
or diluent may include any time delay material, such as
25 glyceryl monostearate or glyceryl distearate, alone or
with a wax. The amount of solid carrier will vary widely
but, preferably, will be from about 25 mg to about 1 9 per
dosage unit. If a liquid carrier is used, the preparation
will be in the form of a syrup, emulsion, soft gelatin
30 capsule, sterile injectable liquid such as an ampule, or
an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparati~ns are made
following conventional techniques of a pharmaceutical
chemist involving mixing, granulating and compressing,
35 when necessary, for tablet forms, or mixing, filling and
~2~QO313
1 dissolving the ingredients, as appropriate, to give the
desired oral or parenteral end products.
Doses of the present compounds in a
pharmaceutical dosage unit will be an effective amount,
that is, a nontoxic quantity selected from the range of
O.1-1,000 mg/kg of active compound, preferably 10-100
mg/kg. The selected dose is administered to a patient in
need of treatment from 1-5 times daily, orally, rectally,
by injection or by infu~ion. Parenteral administration,
10 which uses a low dose is preferred. However, oral
administration, at a higher dose, can also be used when
safe and convenient for the patient.
The following examples are illustrative of
preparation of compounds of the invention (Examples 6-14)
15 or intermediates therefore (Examples 1-5). The starting
compounds of Examples 1-4 are commercially available or
are prepared by known techniques. The examples are not
intended to limit the ~cope of the invention as defined
hereinabove and as claimed below. All temperatures and
20 melting points (mp) are degrees Celsius (C).
EXAMPLE 1
SH
~ / N ~ N
H3C0
A solution of 10 g (.06 mole) of p-methoxyphenyl-
35 isothiocyanate in 100 ml of CHC13 was treated with 6.3 g
lZ 4~ 0 3 -14-
1 (.06 mole) of aminoacetaldehyde dimethyl acetal. The
solvent was evaporated and the residue was recrystallized
from ethanol to yield N-(p-methoxyphenyl)-N'-
~ -dimethoxyethyl)thiourea, 9.2 g (57%). A suspension
of this thiourea in a solution of 5 ml of concentrated
H2S04 and 20 ml of H20 was refluxed for 3 hr. The
mixture wa~ cooled and a solid was filtered, washed with
H2O and dried. Recrystallization from ethanol gave
1-(4-methoxyphenyl)-2-mercaptomidazole, 4.9 9 (70~), mp
10 215-7.
The compound is deprotected as illustrated, for
example, in Example 6, below, to prepare the phenol (Y is
-OH).
EXAMPL~ 2
SH
2~N ~ IY'
,L~ ' \;=./ ' '
H3C0
A mixture of 13.6 g (0.1 mole) of anisaldehyde,
25 13.3 g (0.1 mole) of aminoacetaldehyde diethyl acetal and
1 ml of CH30H was heated at 95 for 10 minutes. A
residue was dissolved in 150 ml of ethanol and
hydrogenated over 10% Pd on carbon at 50 psi (0.34 MPa)
until ~2 uptake was complete. The catalyst was filtered
30 and the filtrate was treated with 10.4 g ~0.107 mole) of
RSCN, 40 ml of 3N HCl and 40 ml of H2O. The mixture was
refluxed, letting the solvent evaporate until the volume
of the reaction mixture was 100 ml. After 45 minutes, the
mixture was cooled, and a solid was filtered, washed with
35 H2O and dried. Recrystallization from ethanol gave
124~L0~)3
--15 -
1 (1-(4-methoxybenzyl)-2-mercaptomidazole, 15.0 g (68%), mp
140-142.
EXAMPLE 3
SH
B ~ \N ~N
A solution of 10.75 g (.05 mole) of 3-bromo-4-
methoxybenzaldehyde and 6.65 g ~.05 mole) of amino-
acetaldehyde diethyl acetal ln 25 ml of ethanol wa~
refluxed for 30 minutes. The solvent was evaporated and
the residue was dissolved in CH2C12. The CH2C12
20 solution of the Schiff base was washed with saturated
aqueous NaCl, dried (X2CO3)and filtered, and the
solvent was evaporated. Residual Schiff base was
dissolved in 100 ml of methanol, cooled to 5, and
treated with 5.0 g of NaBH4. The reaction mixture was
25 allowed to warm to 22 and, after 4 hr, the solvent was
evaporated. The residue was taken up in diethyl ether,
washed with ~2' dried (MgSO4) and filtered, and the
solvent was evaporated. A solution of the residue in
CHC13, upon treatment with ethereal HCl gave, on
30 standing, crystals of N-(3-bromo-4-methoxybenzyl)
aminoacetaldehyde diethylacetal hydrochloride, 10.75 g
(58%), mp. 112-120.
A solution of 10.74 g (.029 mole) of
N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethyl
35 acetal hydrochloride and 3.37 g (0.35 mole) of RSCN in 50
~2~0~)3
--16--
1 ml of H20, 50 ml of ethanol and S ml of 3N HC1 was
refluxed for 4.5 hr. One hundred ml of H20 was added
and the ~ixture was cooled. A solid was filtered, washed
with H20 and dried. Recrystallization from ethanol gave
1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g
(72~), mp 188.
EXAMPLE 4
}O ~ H2~3~N ~ N
CH30
A solution of 12.5 9 (.Q7 mole) of
p-methoxyphenylpropionic acid in 100 ml of CH2C12 and
one drop of pyridine was treated with 9.8 ~ (.077 mole) of
oxalyl chloride. After 2.5 hr, the solvents wer¢
thoroughly evaporated to give the acid chloride as an
oii. A solution of the zcid chloride in 100 ml of
CH2C12 was slowly added to a cold (0) solution of
14.7 g (0.14 mole) of aminoacetaldehyde dimethyl acetal in
300 ml of CH2Cl2 at a rate such that the temperature
stayed below 20. After 1 hr, the reacti~n m$xture was
poured into %2~ and the CH2C12 layer was separated
and washed with aqueous Na2C03, 0.5N HCl and H20.
Following drying and evaporation of the solvent,
N~ dimethoxyethyl)-p-methoxyphenylproponamide was left
as a solid, 10.3 g (55%). A solution of this amide in 300
ml of diethyl ether was slowly added to a slurry of 4.0 9
of LiA1~4 in 400 ml of diethyl ether and 350 ml of
tetrahydrofuran (THF). After 3.5 hr at 22, excess
LiAlH4 was cautiously destroyed, the reaction mixture
was filtered and the filtrate was evaporated. The residue
was dissolved in 100 ml of 0.15N HCl, washed with diethyl
'1 241~3
--17--
1 ether, basified with NaHCO3 and extracted with diethyl
ether. The extracts were dried (MgSO4)and the
solventwas evaporated to give N-[3-(4-methoxyphenyl)-
propyl]-amino-acetaldehyde dimethyl acetal, 4.6 g (52%),
as an unstable oil.
A solution of 3.62 9 (.014 mole) of N-[3-(4-
methoxyphenyl)propyl]dimethyl acetal and 1.4 9 (.0144
mole) of KSCN in 20 ml of ethanol, 5 ml of H20 and 2 ml
of concentrated HCl was refluxed for five hr. Fifty ml of
10 ~2 was added, the mixture was cooled and a solid was
filtered, washed with H20 and dried. Recrystallization
from ethanol gave l-[3-(4-methoxyphenyl) propyl3-2-
mercaptoimidazole, 2.4 g (69~), mp 108-109.
Example 5
CH0
H C3 ~ CH2\N ~ N
A mixture of 15.0 g (0.068 mole) of 1-(4-methoxy-
benzyl)-2-mercaptoimidazole and 80 g of RaneyR nickel in
800 ml of ethanol was refluxed for 4 hr. The nickel was
30 filtered off and the filtrate was evaporated. The residue
was dissolved in 100 ml of lN HCl and this solution was
washed with diethyl ether. The aqueous layer was basified
with ~aHCO3 and extracted with ethyl a~etate. The
extracts were dried (K2CO3), filtered and the solvent
35 was evaporated, to give 1-(4-methoxybenzyl)imidazole as
~2410~3
--18 -
1 an oil, 8.7 9 (68%). A solution of this oil in acetone
was treated with hexamic acid and diethyl ether, and the
!hexamate salt was crystallized, mp 157-159.
A solution of 4.9 g (.026 mole) of 1-(4-methoxy-
benzyl)imidazole in a mixture of lS0 ml of diethyl ether
and 30 ml of tetrahydrofuran (THF) under an atmosphere of
argon was cooled to -60 and treated with 18 ml of a
1.7M solution of n-butyl lithium in hexane. After 1.5 hr,
2.25 g (.031 mole) of dimethylformamide (~MF) was added,
1 and the reaction mixture was warmed to 22. After 30
min, the reaction mixture was treated with 100 ml of l.SN
HCl, and this aqueous mixture was washed with diethyl
ether. The acidic layer was basified with NaHCO3, and
extracted with diethyl ether. The extracts were washed
15 well with H2O, dried (K2CO3), and filtered and the
solvent was evaporated. The residue was a pale yellow
unstable oil, 1-~4-methoxybenzyl) 2-formylimidazole, 4.9 g
(87%).
Ex~
r NH2
~ CH2~ N~N
~0
2HBr
A vigorously stirred suspension of 2.5 9 (.012
mole) of l-(4-methoxybenzyl)-2-formyl imidazole in 30 ml
30 of H2O was treated with 6 g of CH3CO2Na 3H2O and
l.S g of NH2OH HCl. After 2 hr, the 1-(4-methoxybenzyl)-
2-formyl imidazole oxime had solidified. The oxime was
filtered, washed with H2O, dried and recrystallized from
ethanol to give 1.9 g (68%), mp 201-204.
A solution of the oxime in 100 ml of ethanol was
~z4l0n3
--19--
1 hydrogenated over Raney~ nickel at 50 psi tO.34 MPa) for
3 hr. The catalyst was filtered, the filtrate was treated
with ethereal HCl and the solvent was evaporated. The
residue was recrystallized from ethanol three times togive
1-(4-methoxybenzyl)-2-aminomethyl imidazole dihydro-
chloride, 0.53 g (22%). A suspension of this salt in S0
ml of CH2C12 was washed with aqueous NaHCO3. The
CH2C12 solution of the free base was dried (K2CO3)
and filtered. The filtrate was treated with a solution of
10 1.0 9 (.004 mole) of 8Br3 in 2.5 ml of CH2C12.
After 6 hr, methanol was cautiously added and all the
solvents were evaporated. The residue was recrystallized
from a mixture of methanol and diethyl ether to give
1-(4-hydroxybenzyl)-2-aminomethyl imidazole dihydro-
15 bromide, 0.17 g (27%), mp 252-254.
Example 7
r ~Hc6H!;
~ 2 ~ N 2HCl
H3C0
A solution of 1.88 g (.0087 mole) of 1-(4-methoxy-
benzyl)-2-formyl imidazole and 0.81 g (.0087 mole) of
aniline in 20 ml of ethanol was refluxed for 1.5 hr. The
30 reaction mixture was cooled to 22 and treated with 3.0
g of NaBH4. After 3 hr, the solvent was evaporated.
The residue was taken up in diethyl ether, washed with
H2O, dried and filtered and the solvent was evaporated.
The residue was converted to its dihydrochloride salt in a
35 mixture of CH2C12 and ethyl acetate with ethereal HCl,
lz~lon~
1 to give 1-(4-methoxybenzyl)-2-phenylaminomethyl imidazole
dihydrochloride, 1.8 g (56%), mp 146-157.
Example 8
rNHCH,jH5
~ CH2 ~ ~ 2~1Br
H0
A suspension of 1.6 g (.0044 mole) of
15 1-~4-methoxybenzyl)-2-phenylaminomethyl imidazole
dihydrochloride in 100 ml of CH2C12 was converted to
its free ba~e by washing with aqueous NaHCO3. The
CH2C12 was dried (K2CO3), ana filtered, and the
~iltrate was treated with a ~olution o~ 3.3 g (.013 mole)
20 of BBr3 in 9 ml of CH2C12. After 3 hr, methanol was
cautiously added and.all the solvents were evaporated.
The residue was recrystallized from methanol and diethyl
ether to give l-(4-hydroxybenzyl)-2-phenylaminomethyl
imidazole dihydrobromide, 0.73 gm (39~), mp 198-200.
Example 9
C02H
~2~3~ N /~N
H3CO ~ ~ HCl
0~3
-21-
1 A mixture of S.0 9 ~.02 mole) of 1-13-(4-methoxy-
phenyl)propyll-2-mercaptoimidazole~ 40 9 of Rane ~
nickel and 200 ml of ethanol was refluxed for 4 hr. The
Ni was filtered off and the filtrate was evaporated. A
residue was dissolved in 25 ml of lN HCl, and washed with
diethyl ether. The aqueous phase was basified with
aqueous NaHCO3 and extracted with diethyl ether. The
extracts were dried over R2CO3 and filtered, and the
solvent was evaporated. 1-[3-(4-methoxyphenyl)
10 propyl]imidazole remained as an oil, 2.5 q (58%). This
oil was dissolved in 100 ml of diethyl ether and cooled to
-60 under an argon atmosphere. A 1.7M solution of
n-butyl lithium in hexane, 8.2 ml, was added, and the
solution was stirred for 1.5 hr. The argon was replaced
15 with bone dry CO2, and the reaction was stirred
vigorously until CO2 uptake ceased. The reaction
mixture was warmed to 22, and the white lithium salt
was filtered. The f~lter cake was washed with diethyl
ether, and dissolved in 10 ml of H2O. HCl, lN, was
20 added to pH4, at which pH a product crystallized. The
product wa~ filtered, washed with H2O, and dried. The
product was converted to its HCl salt by treatment of an
ethanolic solution of the above filtered material with
ethereal HCl and diethyl ether. The resultant 1-[3-(4-
25 methoxyphenyl)propyl]imidazole-2-carboxylic acid
hydrochloride was 1.2 g (35%), mp 130 (dec).
Example 10
3 o ~/ N - N
1.2~2!~)3
1 Substantially by the procedure of Example 9,
except that the starting mercaptoimidazole was 1-(4-
methoxybenzyl)mercaptoimidazole, the compound 1-(4-
methoxybenzyl)imidazole-2-carboxylic acid hydrochloride,
m.p. 115 (dec), was prepared.
Example 11
C02H
J~ ~=~
H0 . ~ H20
A suspension of 1.1 g (.0037 mole) of
1-~3-~4-methoxyphenyl)propyl]imidazole-2-carboxylic acid
hydrochloride in 100 ml of CH2C12 at 5 wa~ treated
with a solution o 2.8 g ~.011 mole) of BBr3 in 7 ml of
CH2C12. The mixture was allowed to warm to 22, and
stirred for 5 hr. Methanol was cautiously added, and when
a virgorou~ reaction was over, all solvents were
evaporated. A residue was dis~olved in 10 ml of H2O and
the pH was adjusted to 3.5 with aqueous NaHCO3. The
product crystallized, was filtered, washed with H2O and
dried. RecrystallizatiOn from methanol gave 1-[3-
(4-hydroxyphenyl)propyl]imidazole-2-carboxylic acid,
hemihydrate, 0.65 g (71%), mp 136 (dec).
Example }2
CO2H
~ / CH2~ ~
Y . - N N
~ ~ l ~ ~ ~2
3~ .
-23-
1 241Q03
1 Substantially by the procedure of Example 9,
except that the starting mercaptoimidazole was
1-(4-methoxybenzyl) mercaptoimidazole, the compound
1-(4-methoxybenzyl)imidazole-2-carboxylic acid, hydro-
chloride, mp 115, was prepared. Substantially
following the procedure of Example 11, the carboxylic acid
was converted to l-(4-methoxybenzyl)imidazole-2-carboxylic
acid hydrochloride hydrate, m.p. 135-142 (dec).
Example 13
CH2~1t2
¢~4~ /~
Substantial}y by the procedure of 2xample 5,
except that the starting mercaptolmldazole was 1-benzyl-2-
mercaptoimidazole, a commercially available compound,
the compound, 1-benzyl-2-formyl imidazole, was prepared.
Substantially following the procedure of Example 6, the
benzyl imidazole was converted to l-benzyl-2-aminomethyl
imidazole dihydrochloride, mp 185-187.
Example 14
r~c6~
~4~ /~
W
Substantially by the procedure of Example 5,
except that the starting mercaptoimidazole was 1-benzyl-2-
i Z 4 1 0 ~ 3 -24-
1 mercaptoimidazole, a commercially available compound, the
compound, l-benzy}-2-formyl imidazole, was prepared.
Substantially following the procedure of Example 7, the
benzyl imidazole was converted to l-benzyl-2-benzyl
aminomethyl imidazole dihydrochloride, m.p. 206.
While the preferred embodiments of the invention
are illustrated by the above, it is to be understood that
the invention is not limited to the precise constructions
herein disclosed and that the right to all modifications
coming within the scope of the following claims is
reserved.
