Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Pyrimidine Derivatives
This application claims the benefit of U.S. Provisional
Application No. 60/057,472, filed September 3, 1997.
The present invention relates to novel pyrimidine
derivatives, to processes for preparing them, to
intermediates useful in preparing them, to pharmaceutical
compositions containing them and to uses for them as
pharmaceuticals.
United States patent number 4,323,570 discloses a group
of aminopyrimidine derivatives having antihypertensive
activity. One of the compounds, 4-chloro-5-(imidazoline-2-
ylamino)-6-methoxy-2-methylpyrimidine, is commercially
available in some countries under the generic name
moxonidine for the treatment of hypertension. This compound
may interconvert with its tautomer, 4-chloro-5-
(imidazolidin-2-ylideneimino)-6-methoxy-2-methylpyrimidine.
We have now found a novel pyrimidine derivative having
a 2-hydroxymethyl substituent which possesses anti-
hypertensive activity.
The present invention provides a compound of formula
Re
N
HO ~~NH
N ~~
Rb HN
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in which each of Ra and Rb independently represents a C1-C6
alkoxy group or a halogen atom; a pharmaceutically
acceptable metabolically labile ester or amide thereof; or a
pharmaceutically acceptable salt of said compound, said
ester or said amide.
The compound 2-hydroxymethyl-4-chloro-5-(imidazolidin-
2-ylidene)-6-methoxypyrimidine has been found to lower blood
pressure and heart rate when administered intravenously to
spontaneously hypertensive rats at a dose of 3 mg/kg when
tested according to the method described by A. D. Palkowitz
et al., J. Med. Chem., Vol. 37, p. 4508-4521, 1994.
It will be appreciated by those skilled in the art that
the compounds of formula I can exist in tautomeric form as
shown below.
Ra
N _
HO \~NH ~ i HO ~ -N
N
HN Rb HN
The invention includes each tautomeric form of the
compound.
Pharmaceutically acceptable salts of the compound of
formula I include acid addition salts formed with inorganic
acids such as hydrochloric, hydrobromic, hydriodic, sulfuric
and phosphoric acid, as well as organic acids such as para-
toluenesulfonic, methanesulfonic, oxalic, para-
bromophenylsulfonic, carbonic, succinic, citric, benzoic,
and acetic acid, and related inorganic and organic acids.
The pharmaceutically acceptable salts thus include the
hydrogen chloride, hydrogen bromide and hydrogen iodide acid
addition salts.
Pharmaceutically acceptable metabolically labile ester
and amides of the compound of formula I are ester or amide
derivatives of the compound of formula I that are hydrolyzed
in vivo to afford the compound of formula I and a
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pharmaceutically acceptable carboxylic acid. Examples of
labile esters include esters formed with the hydroxyl group
in the compound of formula I and an alkanoic acid, such as
acetic acid. Example of metabolically labile amides include
amides formed with an NH group in the compound of formula I
and an alkanoic acid such as acetic acid.
A particular value for a C1-C6 alkoxy group represented
by Ra or Rb is methoxy.
A particular value for a halogen atom represented by Ra
or Rb is chlorine.
Preferably Ra represents methoxy and Rb represents
chlorine.
A particularly preferred compound is 2-hydroxymethyl-4-
chloro-5-(imidazolidin-2-ylidene)-6-methoxypyrimidine.
The compound 2-hydroxymethyl-4-chloro-5-(imidazolidin-
2-ylidene)-6-methoxypyrimidine was originally isolated as a
metabolite of moxonidine from the urine of rats and dogs.
Another aspect of the invention is, therefore, a compound of
formula I in a pharmaceutically acceptable state of purity.
The compounds according to the invention may also be
prepared by a process which comprises:
(a) reacting a compound of formula
N
CH2 ~ ~z
Ry II
N
Rb
or a salt thereof, with a compound of formula
R2
N
O
III
N
H
Ra
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in which R1 represents a hydrogen atom or a hydroxyl
protecting group and R2 represents a hydrogen atom or an
amino protecting group; or
(b) reducing a compound of formula
Ra
N-
3
R ~ ~ N \ ~2 IV
N
Rb HN
in which R3 represents a carboxyl group or an ester
derivative thereof, or a salt thereof;
to afford a compound of formula
Ra
N-
Rz
R10CH2 \ ~ N ~ N
N Ia
Rb HN
of a salt thereof;
whereafter, as necessary, optionally
(i) replacing a halogen atom represented by Ra or Rb with
a C1-C6 alkoxy group by reaction with a C1-C6 alkanol in the
presence of a base; and further optionally
(ii) removing any remaining protecting groups; and further
optionally
(iii) forming a pharmaceutically acceptable metabolically
labile ester or amide; or
(iv) forming a pharmaceutically acceptable salt.
The protection of hydroxyl and amino groups, is
generally described in McOmie, Protecting Groups in Organic
Chemistry, Plenum Press, NY, 1973, and Greene and Wuts,
Protecting Groups in Organic Synthesis, 2nd. Ed., John wiley
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& Sons, NY, 1991. Examples of hydroxyl protecting groups
include acyl groups, such as groups of formula R4C0 in which
R4 represents C1-C6 alkyl, (3-10C) cycloalkyl, phenyl C1-C6
alkyl, phenyl, C1-C6 alkoxy, phenyl C1-C6 alkoxy, or (3-10C)
cycloalkoxy, wherein a phenyl group may be unsubstituted or
substituted by one or two substituents independently
selected from amino, hydroxy, nitro, halogeno, C1-C6 alkyl,
C1-C6 alkoxy, carboxy, C1-C6 alkoxycarbonyl, carbamoyl,
C1-Cg alkanoylamino, C1-C6 alkylsulphonylamino, phenyl-
sulphonylamino, toluenesulphonylamino, and C1-C6 fluoro-
alkyl. Examples of amine protecting groups include acyl
groups of formula R5C0, in which R5 is as defined for R'~.
Examples of particular values for R1 and R2 are
hydrogen and C1-C6 alkanoyl such as acetyl.
Examples of particular values for R3 are carboxy and
C1-C6 alkoxycarbonyl such as methoxycarbonyl or
ethoxycarbonyl.
In process step (a), the compound of formula II is
conveniently reacted with the compound of formula III in the
presence of a dehydrating agent, such as phosphorous
oxychloride. The reaction is conveniently conducted at a
temperature in the range of from 20 to 150~C, preferably at
90 to 110~C. An excess of phosphorous oxychloride may be
used as reaction solvent.
The reduction process step (b) may conveniently be
performed using a reducing agent such as lithium aluminum
hydride. Suitable solvents include ethers such as
tetrahydrofuran.
In the replacement of a halogen atom with an alkoxy
group, the base is conveniently an alkali metal alkoxide,
such as a sodium alkoxide or potassium alkoxide. The
reaction is conveniently performed in an alkanol as a
reaction solvent, and under reflux conditions.
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Any protecting groups may conveniently be removed
employing a method well known in the art. For example, an
aryl group protecting the hydroxyl or an amino group may
conveniently be removed by acid or base catalyzed hydrolysis
or methanolysis, for example by reaction with methanol in
the presence of an alkali metal methoxide. In this
connection, it will be appreciated that an acyl group
protecting the hydroxyl or an amino group in a compound of
formula Ia may be removed during the replacement of a
halogen atom with an alkoxy group.
Pharmaceutically acceptable metabolically labile esters
or amides of the compound of formula I, and pharmaceutically
acceptable salts thereof may be prepared by methods well
known in the art.
The compounds of formula IV may be prepared by reacting
a compound of formula
Ra
N-
R3 ~ ~ NH2
N V
Rb
or a salt thereof with a compound of formula III, following
the method of process step (a).
The compounds of formula II and V may be prepared by
reducing a compound of formula
Ra
N-
R6 ~ ~ N02
N VI
Rb
in which R6 represents R10CH2 or R3, as appropriate. The
reduction is conveniently performed using hydrogen and a
group VIII metal catalyst, for example Raney nickel.
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The compounds of formula VI may be prepared by reacting
a compound of formula
OH
N-
R6 ~ ~ N02
N VII
OH
with a halogenating agent, for example a phosphorus
oxyhalide. The reaction is conveniently performed in the
presence of a base, such as N,N-diethylaniline. One or two
atoms may subsequently be replaced with alkoxy by reaction
with an alkali metal alkoxide in an alkanol.
The compounds of formula VII may be prepared by
reacting a compound of formula
OH
N-
Rs
VIII
N
OH
with a nitrating agent, for example a mixture of fuming
nitric acid and glacial acetic acid.
The compounds of formula VIII may be prepared by
reacting a compound of formula
NH
R6-IC
\ IX
~2
or a salt thereof, such as the hydrochloride with a
malonate, such as diethylmalonate, in the presence of a
strong base, such as an alkali metal alkoxide, for example
sodium ethoxide.
The compounds of formula III and IX are known, for
example from US 4,323,570, or may be prepared by well-known
methods.
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Certain intermediates described herein, for example the
compounds of formula TV are believed to be novel and are
provided as further aspects of the invention.
The compounds according to the invention are preferably
formulated in a pharmaceutical composition prior to
administration.
According to another aspect, therefore, the present
invention provides a compound of formula I, a
pharmaceutically acceptable metabolically labile ester or
amide thereof, or a pharmaceutically acceptable salt
thereof, in combination with a pharmaceutically acceptable
diluent or carrier.
The pharmaceutical compositions may be prepared by
known procedures using well-known and readily available
ingredients. In making the compositions of the present
invention, the active ingredient will usually be mixed with
a carrier, or diluted by a carrier, or enclosed within a
carrier, and may be in the form of a capsule, sachet, paper,
or other container. When the carrier serves as a diluent,
it may be a solid, semi-solid, or liquid material which acts
as a vehicle, excipient, or medium for the active
ingredient. The compositions can be in the form of tablets,
pills, powders, lozenges, sachets, cachets, elixirs,
suspensions, emulsions, solutions, syrups, aerosols,
ointments containing, for example, up to 10% by weight of
active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile
packaged powders.
Some examples of suitable carriers, excipients, and
diluents include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum, acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate, micro-
crystalline cellulose, polyvinylpyrrolidone, cellulose,
water syrup, methyl cellulose, methyl and propyl hydroxy-
benzoates, talc, magnesium stearate, and mineral oil. The
formulations can additionally include lubricating agents,
wetting agents, emulsifying and suspending agents,
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preserving agents, sweetening agents, or flavoring agents.
Compositions of the invention may be formulated so as to
provide quick, sustained, or delayed release of the active
ingredient after administration to the patient by employing
procedures well known in the art.
The compositions are preferably formulated in a unit
dosage form, each dosage containing from about 5 mg to about
500 mg, more preferably about 25 mg to about 300 mg of the
active ingredient. The term "unit dosage form" refers to a
physically discrete unit suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association with
a suitable pharmaceutical carrier, diluent, or excipient.
The following formulation example is illustrative only and
is not intended to limit the scope of the invention in any
way.
Formulation
Example
Tablets each containing 60 mg of active ingredient are made
as follows:
Active Ingredient 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mct
Total 150 mg
The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The
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solution of polyvinylpyrrolidone is mixed with the resultant
powders which are then passed through a No. 14 mesh U.S.
sieve. The granules so produced are dried at 50~C and
passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc,
previously passed through a No. 60 mesh U.S. sieve, are then
added to the granules which, after mixing, are compressed on
a tablet machine to yield tablets each weighing 150 mg.
The compounds according to the invention are useful in
the treatment of hypertension, congestive heart failure,
non-insulin dependent diabetes mellitus, smoking cessation,
nicotine withdrawal, opioid withdrawal, ethanol withdrawal
and atherosclerosis. According to other aspects of the
invention therefore, the present invention provides the use
of the compounds of the invention for the treatment of each
of the conditions in a warm blooded mammal, such as a human.
The following example illustrates the invention.
Example
Biological Activity in Hypertensive Rats
Telemetry Implantation
Spontaneously hypertensive rats (Tac:N(SHR)fBR) were
obtained from Taconic Farms (Germantown, NY) at 14-16 weeks
of age (295-325 gm) and housed under a 12-hour light/dark
cycle (lights on from 0600 to 1800 hours). Following a 1-
week acclimation period, rats were anesthetized with 20
isoflurane (Aerrane, Anaquest, Madison, WI) for implantation
of blood pressure transmitters (model TAlIPA-C40, Data
Sciences Int (DSI), St Paul, MN) as follows: The abdomen was
shaved, scrubbed with Betadine~, and a 4.5-cm abdominal
incision was made beginning just caudal to the approximate
location of the kidneys. The abdominal aorta was isolated
and gently cleaned of connective tissue with a sterile
cotton swab. A small spatula was used to raise a portion of
the aorta away from the vena cava in an area just rostral to
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the iliac artery bifurcation. A bulldog clamp was placed
caudal to the left renal artery, and the aorta was punctured
rostral to the common iliac using a 21-gauge needle (bent at
a 45~ angle with the bevel down). A fluid-filled catheter
(0.7 mm OD, 8 cm in length) attached to the hermetically
sealed transmitter was inserted and advanced to the bulldog
clamp using the bent needle as a guide. The area was dried
with a cotton swab and tissue adhesive applied at the entry
point while the clamp was removed. The entry point was
further sealed using tissue adhesive and a cellulose fiber
patch (Vetland, 3M Co). The body of the transmitter was
sutured to the muscles of the inner abdominal wall using
non-absorbable 4-0 silk, the muscle layers were approximated
with sterile 3-0 silk, and the final incision closed with
sterile metal wound clips. A11 animals were administered
10,000 units of penicillin intramuscularly (Ambi-Pen~,
Butler), housed individually in shoe box cages with food and
water ad libitum, and permitted to recover fox at least one
week before study. Digitized pressure signals were acquired
for 30 seconds every 10 minutes using DSI Dataquest IV 2.0
software. Mean pressure was calculated as the arithmetic
mean of the sample waveform sampled at a frequency of 500
Hz. The digitized values were stored and manipulated on a
Compac Deskpro 486/33MHz computer.
Protocol
Animals were briefly sedated with 2% isoflurane. Test
compounds or vehicle were administered via the tail vein in
a total volume of 0.3-0.4 ml. The hydroxymethyl metabolite
was administered in a water vehicle made by adding
approximately 50 ~I of 1N HCL to the metabolite base and
slowly diluting with water to appropriate concentration.
Rats were then returned to telemetry cages and blood
pressure was monitored for the subsequent 24 hours.
Monitoring was initiated immediately except that the values
for 15 min prior and subsequent to dosing were omitted.
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Results
The hydroxymethyl metabolite lowered mean blood
pressure compared to vehicle in the SHR.
Table 1
Time Hydroxymethyl
(hours)MAP Metabolite Vehicle
1.00 -l5.80 10.10
2.00 -16.80 0.40
3.00 -9.40 4.00
4.00 -8.50 0.90
5.00 -7.80 -3.40
6.00 -7.80 -4.00
7.00 -7.00 -l.80
8.00 -5.80 -1.90
9.00 -5.20 5.60
l0.00 -4.20 2.30
11.00 -2.60 -0.70
12.00 -7.50 1.80
13.00 -6.00 -0.10
14.00 -6.30 -0.60
15.00 -3.80 1.80
16.00 -4.50 -l.20
l7.00 -3.00 -2.50
18.00 -5.60 2.l0
19.00 -1.80 0.80
20.00 -4.50 2.20
21.00 -2.50 -1.60
22.00 -13.30 -l.10
23.00 -9.80 -5.20
_ ( -9.80 J -2.90
24.00
The effect of the hydroxymethyl metabolite lasted for
approximately 4 hours. Accompanying the effect of
hydroxymethyl metabolite on blood pressure was pronounced
falls in heart rate (Table 2) that were most prominent 4
hours after dosing.
Table 2
Time Hydroxymethyl
(hours) H Metabolite Vehicle
r
1.00 -32.10 24.90
2.00 -2.40 4.00
3.00 8.70 2.50
4.00 6.20 -1.90
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5.00 18.10 0.80
6.00 6.40 -8.30
7.00 7.20 4.70
8.00 21.40 16.60
9.00 23.20 39.50
10.00 32.80 41.50
11.00 37.00 46.50
12.00 36.80 36.50
l3.00 25.80 33.60
14.00 31.00 34.40
15.00 29.80 20.80
16.00 37.00 31.10
17.00 12.70 23.40
18.00 7.60 12.60
l9.00 24.50 24.90
20.00 25.80 19.60
21.00 6.10 16.80
22.00 -7.20 10.10
23.00 -10.80 -l7.60
24.00 1.40 -10.00
Consistent with the shorter effect of the hydroxymethyl
metabolite on blood pressure, there was also a significant
fall compared to vehicle in heart rate apparent during the
first hour after dosing.
Conclusion
The moxonidine hydroxymethyl metabolite has been
identified in urine of rats, dogs, mice and humans.
Moxonidine and the hydroxymethyl metabolite are shown to be
analagous in that they both possess antihypertensive and
bradycardic activity in conscious unrestrained hypertensive
rats. This analogy can also be drawn from moxonidine to the
hydroxymethyl metabolite in other treatments, as well, as
would be apparent to those skilled in the art. Moxonidine
has been shown to be an effective treatment for hypertension
(U. S. Patent No. 4,323,570), smoking cessation, nicotine
withdrawal, opioid withdrawal, ethanol withdrawal (U. S.
Patent No. 5,732,7l7), congestive heart failure (PCT
publication W097/46241), non-insulin dependent diabetes
(U. S. Patent No. 5,7l2,283), and atherosclerosis (PCT
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publication W096/26728). Therefore, another embodiment of
this invention is the use of a compound of the formula
Ra
N
HO _ ~~NH
~N
Rb HN
in which each of Ra and Rb independently represents a C1-C6
alkoxy group or a halogen atom; a pharmaceutically
acceptable metabolically labile ester or amide thereof; or a
pharmaceutically acceptable salt of said compound, said
ester or said amide for the treatment of hypertension,
smoking cessation, nicotine withdrawal, opioid withdrawal,
ethanol withdrawal, congestive heart failure, non-insulin
dependent diabetes, and atherosclerosis.
The particular dose of compound administered according
to this invention for the treatment of the indications alone
or in combination will of course be determined by the
particular circumstances surrounding the case, including the
compound administered, the warm blooded mammal being
treated, the route of administration, the particular
condition being treated, and similar considerations. The
compounds can be administered by a variety of routes
including oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular, or intranasal routes.
Alternatively, the compound may be administered by
continuous infusion. A typical daily dose will contain from
0.005 mg/kg to 50 mg/kg of the active compound of this
invention. Preferably, daily doses will be 0.01 mg/kg to 25
mg/kg, more preferably from 0.1 mg/kg to 10 mg/kg.
The following Example illustrates the invention.
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Example 1
2-Hydroxymethyl-4-chloro-5-(imidazolin-2-ylideneimino)-6
methoxypyrimidine
(a) Preparation of 4,6-dihydroxy-2-hydroxymethylpyrimidine:
To a solution of sodium ethoxide prepared from sodium
(1.38 g, 60.0 mmol) and ethanol (29 mL), was added
hydroxyacetamidine hydrochloride (McCasland, G, E. and
Tarbell, S. - J. Amer. Chem. Soc., l946, 68, 2393-2395)
(2.21 g, 20.0 mmol) and after 5 min ethyl malonate (3.2 g,
20.0 mmol). The reaction mixture was refluxed for 3 hours
then cooled to roam temperature, diluted with water (10 mL)
and acidified with concentrated hydrochloric acid (4 mL).
The precipitate was filtered off, washed with water (10 mL),
ethanol (5 mL) and ether (5 mL), and dried under vacuum to
give 2.24 g (79%) of the title compound as a light-brown
solid. IR (KBr): 527, 1106, l324, 1571, l639, 1682, 2910,
3029, 3084 cm-1~, W (EtOH) ~, max(s): 256 (4235), 239 nm
(3398); 1H-NMR (DMSO-d6) 8 4.28(s), 5.14(s), 5.66(s);
MS (FD) : 142 (M', l00%) .
(b) Preparation of 4,6-dihydroxy-2-hydroxymethyl-5-
nitropyrimidine:
To a stirred mixture of nitric acid (fuming, 4.2 mL)
and acetic acid (glacial, 2.1 mL) was added the product of
Step (a) (2.3 g, 16.2 mmol) over the period of 40 min at 10-
15~C. The reaction mixture was stirred for 5.5 hours at
room temperature then cooled down to 5~C and diluted with
cold water (3 mL). The precipitate was collected by
filtration, washed with ethanol (5 mL) and ether (5 mL), and
dried under vacuum to give 2.44 g (80.5%) of title compound
as a colorless solid. IR (KBr): 539, 789, 1105, 1297, 1358,
1630, l674, 2828, 2920, 3402, 3460 cm-1~, UV (EtOH)
max(s) : 322 (3354) , 213 nm (17626) ; 1H-NMR (DMSO-d6) 8 4.42
(s,CH2) ; MS (FD) : 187 (M', 100%) .
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(c) Preparation of 2-acetoxymethyl-4,6-dihydroxy-5-
nitropyrimidine:
A mixture of the product of Step (b) (2.35 g, I2.56
mmol), acetic acid (glacial, 15 mL), and acetic anhydride
(15 mL) was heated at 105~C for 2 hours, then evaporated
under vacuum, and re-evaporated with toluene (3 times). The
residue was dried under vacuum to give 2.843 g (990) of
title compound as a yellow solid. IR (KBr): 545, 787, 12l2,
1326, 1354, 1367, l493, 1650, 1673, l758, 2939, 3082, 3141
cm-1 ~ , UV (EtOH) ~, max(s) : 327 nm (3365) ; 1H-NMR (DMSO-d6) 8
2.14 (s, 3H, CH3), 4.98 (s, 2H, CH2); MS (FD): 229 (M',
100%) .
(d) Preparation of 2-acetoxymethyl-4,6-dichloro-5-
nitropyrimidine:
To a mixture of the product of Step (c) (2.75 g, 12.0
mmol) and phosphorus oxychloride (13 mL) was added N,N-
diethylaniline (2.5 mL, 15.7 mmol) dropwise. The reaction
mixture was refluxed for 2 hours and evaporated under
vacuum. The residue was diluted with ether t15 mL) and
poured onto ice. After stirring for 3 min organic layer was
separated, washed with saturated aqueous solutions of sodium
bicarbonate and sodium chloride, then dried over sodium
sulfate and evaporated under vacuum. Flash chromatography
of the residue on silica gel (20% ether in hexane) gave
2.446 g (77%) of title compound as a white solid, Rf 0.60
(hexanefethyl acetate, 3:2). IR (KBr): 836, 853, 1218,
1550, 1755 cm-1~, UV (EtOH) ~, max(s): 259 nm (3290); 1H-NMR
(CDC13) 8 2.28 (s, 3H, CH3)) 5.33 (s , 2H, CH2). Analysis
calculated for C7H5C12N304: C, 31.60; H, 1.89; N, 15.79.
Found: C, 31.84; H, 1.85; N, 15.69.
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(e) Preparation of 2-acetoxymethyl-4,6-dichloro-5-
aminopyrimidine:
A mixture of the product of Step (d) (255 mg, 0.96
mmol) and Raney nickel (30 mg) in ethanol (25 mL) was
hydrogenated in Parr apparatus (50 pSi of hydrogen) for 5.5
h. The resulting suspension was filtered through celite and
evaporated under vacuum. Flash chromatography of the
residue on silica gel (40o ethyl acetate in hexane) gave 202
mg (89%) of title compound as a colorless solid, Rf 0.41
(hexane/ethyl acetate, 3:2). IR (KBr): 793, 907, 1249,
1366, 1459, 1513, 1621, l731, 3332, 3428 cm-1~, UV (EtOH) ~,
max(e): 314 (5676), 253 nm (11629); 1H-NMR (CDC13) 8 2.21
(s, 3H, CH3) , 4.55 (s, 2H, NH2) , 5.l6 (s, 2H, CH2) ; MS (FD)
235 iM+, l00%) .
(f) Preparation of 2-acetoxymethyl-4,6-dichloro-5-(1-
acetylimidazolidin-2-ylidenimino)pyrimidine:
To a solution of the product of Step (e) (191 mg, 0.8l
mmol) in phosphorus oxychloride (1 mL) was added N-acetyl-2-
imidazolidone (1l4 mg, 0.89 mmol) in one portion. The
reaction mixture was heated at 105-110~C (bath) for 3 hours
and evaporated under vacuum. The residue was diluted with
ice water (2 mL), made alkaline with aqueous sodium
hydroxide (5N, 2 mL) and extracted with dichloromethane (3 x
5 mL). The extract was washed with saturated aqueous
solutions of sodium bicarbonate and sodium chloride, dried
over sodium sulfate and evaporated under vacuum. Flash
chromatography of the residue on silica gel (from 50 to 60%
of ethyl acetate in hexane) gave l66 mg (590) of title
compound as a colorless solid, Rf 0.21 (hexane/ethyl
acetate, 1:1). IR (KBr): 815, l033, 1074, 1219, l355, 1378,
1414, 1497, 1657, 1675, 1752, 3254, cm-1~, UV (EtOH)
max(E): 245 nm (12Z18); 1H-NMR (CDC13) 8 2.23 (s, 3H,
CH3C00), 2.70 (s, 3H, CH3CON), 3.58 (t, J = 7.98 Hz, 2H,
CA 02269971 1999-04-27
WO 99/11269 PCT/US98/18381
-18-
CH2N), 4.11 (t, J = 7.98 Hz, 2H, CH2N), 4.74 (s, 1H, NH),
5.l9 (s, 2H, CH20); HRMS (FAB): calculated for
C12H13C12N503= 346.0474. Found: 346.0481.
(g) Preparation of 2-hydroxymethyl-4-chloro-5-
(imidazolidin-2-ylidenimino)-6-methoxypyrimidine
A solution of the product of Step (f) (87 mg, 0.25
mmol) and sodium methoxide (14 mg, 0.26 mmol) in methanol
(1.2 mL) was refluxed for 3 hours. The reaction mixture was
evaporated under vacuum to one half of the initial volume
and cooled to 5~C. The precipitate was collected by
filtration, washed with water (1 mL) and dried under vacuum
to give 32 mg (50%) of title compound as a colorless solid.
IR (KBr): 720, 1042, 1091, 1283, 1307, 1376, 1440, 1471,
1533, 1659, 3030, 3225, 3340 cm-1~, UV (EtOH) ~, max(s): 254
nm (8577); 1H-NMR (DMSO-d6) 8 3.34 (s, 4H, CH2N), 3.87 (s,
3H, CH3), 4.39 (d, J = 6.18 Hz, 2H, CH20), 5.19 (t, J = 6.18
Hz, 1H, OH), 6.26 (s, 2H, NH), HRMS (FAB): calculated for
CgH12C1N502: 258.0758. Found: 258.0759.
