Disclosed herein are 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids and pharmaceutically acceptable salts thereof and methods of their preparation. The compounds are new aldose reductase inhibitors useful for the treatment or prevention of diabetic complications.

BACKGROUND OF THE INVENTION 
This invention relates to 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic 
acids, to pharmaceutical salts thereof, to the processes for their 
preparation, and to methods for using these compounds. The compounds have 
pharmaceutical properties which render them beneficial for the treatment 
or prevention of diabetic complications. 
For many years diabetes mellitus has been treated with two established 
types of drugs, namely insulin and oral hypoglycemic agents. These drugs 
have benefited hundreds of thousands of diabetics by improving their 
well-being and prolonging their lives. However, the resulting longevity of 
diabetic patients has led to complications such as neuropathy, 
nephropathy, retinopathy, cataracts, and atherosclerosis. These 
complications have been linked to the undesirable accumulation of sorbitol 
in diabetic tissue, which in turn results from the high levels of glucose 
characteristic of the diabetic patient. 
In mammals, including humans, the key enzyme involved in the conversion of 
hexoses to polyols (e.g. the sorbitol pathway) is aldose reductase. J. H. 
Kinoshita and collaborators (see J. H. Kinoshita et al, Biochem. Biophys. 
Acta, 158, 472 (1968) and references cited therein) have demonstrated that 
aldose reductase plays a central role in the etiology of galactosemic 
cataracts by effecting the conversion of galactose to dulcitol 
(galactitol); and that an agent capable of inhibiting aldose reductase can 
prevent the detrimental accumulation of dulcitol in the lens. Furthermore, 
a relationship between elevated levels of glucose and an undesireable 
accumulation of sorbitol has been demonstrated in the lens, peripheral 
nervous cord, and kidney of diabetic animals, (see A. Pirie and R. van 
Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylack and J. H. 
Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. 
Baker, Diabetol., 6, 531 (1970)). 
N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methylglyc 
ine has been reported to be an effective inhibitor of aldose reductase, see 
K. Sestanj et al, U.S. Pat. No. 4,568,693, Feb. 4, 1986. The present 
invention discloses novel 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic 
acids which unexpectedly show aldose reductase inhibitory activity. Up to 
now, amino-pyrimidine derivatives have been reported to be useful for 
increasing cardiac contractility, see J. Bagli et al, U.S. Pat. Nos. 
4,505,910, Mar. 19, 1985, and 4,617,393, Oct. 14, 1986. 
SUMMARY OF THE INVENTION 
The 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acid of this invention 
are represented by formula (I) 
##STR1## 
wherein R.sup.1 is lower alkyl containing 1 to 6 carbon atoms, 
cyclo(lower)alkyl containing 3 to 6 carbon atoms, phenyl, halogen 
substituted phenyl, phenylmethyl, naphthalenyl, halogen substituted 
naphthalenyl, or thienyl; R is --SR.sup.2 wherein R.sup.2 is lower alkyl 
containing 1 to 6 carbon atoms, lower cycloalkylmethyl containing 4 to 7 
carbon atoms, phenylmethyl, or halogen substituted phenylmethyl; or R is 
R.sup.3 wherein R.sup.3 is lower alkyl containing 1 to 4 carbon atoms, 
phenyl, or 1-naphthalenylmethyl; and the pharmaceutically acceptable salts 
thereof. 
A preferred aspect of the present invention is the compounds of formula (I) 
wherein R.sup.1 is 1-methylethyl, 1,1-dimethylethyl, propyl, 
2,2-dimethylpropyl, phenyl, 4-bromophenyl, naphthalenyl, 
5-bromonaphthalenyl, or 2-thienyl; R is --SR.sup.2 wherein R.sup.2 is 
methyl, 1-methylethyl, hexyl, cyclohexylmethyl, phenylmethyl, 
4-bromophenylmethyl, or 4-bromo-2-fluorophenylmethyl; or R is R.sup.3 
wherein R.sup.3 is methyl, 1-methylethyl, phenyl, or 1-naphthalenylmethyl; 
and the pharmaceutically acceptable salts thereof. 
A still further preferred aspect of the present invention is the compounds 
of formula (I) wherein R.sup.1 is 1,1-dimethylethyl or 
5-bromonaphthalenyl; R is --SR.sup.2 wherein R.sup.2 is methyl, hexyl, 
cyclohexylmethyl, or phenylmethyl; or R is R.sup.3 wherein R.sup.3 is 
1-naphthalenylmethyl; and the pharmaceutically acceptable salts thereof. 
The most preferred compounds of the present invention are 
[[5-cyano-6-[(cyclohexylmethyl)thio]-2-(1,1-dimethylethyl)-4-pyrimidinyl]o 
xy]acetic acid; and 
[[2-(5-bromo-1-naphthalenyl)-5-cyano-6-[(1-naphthalenyl)methyl]-4-pyrimidi 
nyl]oxy]acetic acid; and the pharmaceutically acceptable salts thereof. 
The 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids, and the 
pharmaceutically acceptable salts thereof can be prepared by the processes 
described hereinafter. 
A method is provided for preventing or relieving diabetes mellitus 
associated complications in a diabetic mammal by administering to said 
mammal a prophylactic or alleviating amount of a compound of formula (I). 
Such complications include neuropathy, nephropathy, retinopathy, and 
cataracts. 
The compounds of formula (I), when admixed with a pharmaceutically 
acceptable carrier, form a pharmaceutical composition which can be used 
according to the preceding method.

DETAILED DESCRIPTION OF THE INVENTION 
The compounds of formula (I) form salts with suitable therapeutically 
acceptable inorganic and organic bases. These derived salts possess the 
same activity as their parent acid and are included within the scope of 
this invention. The acid is transformed in excellent yield into the 
corresponding therapeutically acceptable salt by neutralization of said 
acid with the appropriate inorganic or organic base. The salts are 
administered usually in the same manner as the parent acid compounds. 
Suitable inorganic bases to form these salts include, for example, the 
hydroxides, carbonates, or bicarbonates of the therapeutically acceptable 
alkali metals or alkaline earth metals, for example, sodium, potassium, 
magnesium, calcium, and the like. Suitable organic bases include the 
following amines: benzylamine; lower mono-, di- ior trialkylamines, the 
alkyl radicals of which contain up to three carbon atoms, such as 
methylamine, dimethylamine, trimethylamine, ethylamine, di- and 
triethylamine, methylethylamine, and the like; mono-, di- and 
trialkanolamines, the alkanol radicals of which contain up to three carbon 
atoms, for example, mono-, di- and triethanolamine; alkylene-diamines 
which contain up to six carbon atoms, such as hexamethylenediamine; cyclic 
saturated or unsaturated bases containing up to six carbon atoms, such as 
pyrrolidine, piperidine, morpholine, piperazine, and their N-alkyl and 
N-hydroxyalkyl derivatives, such as N-methyl-morpholine and 
N-(2-hydroxyethyl)-piperidine, as well as pyridine. Furthermore, there may 
be mentioned the corresponding quaternary salts, such as the tetraalkyl 
(for example, tetramethyl), alkyl-alkanol (for example, methyltriethanol 
and trimethyl-monoethanol), and cyclic ammonium salts, for example, the 
N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, 
N,N-dimethylmorpholinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, 
N,N-dimethylpiperidinium salts, which are characterized by having good 
water-solubility. In principle, however, there can be used all the 
ammonium salts which are physiologically compatible. 
The transformations to the salts can be carried out by a variety of methods 
known in the art. For example, in the case of the inorganic salts, it is 
preferred to dissolve the acid of formula (I) in water containing at least 
one equivalent amount of a hydroxide, carbonate, or bicarbonate 
corresponding to the inorganic salt desired. Advantageously, the reaction 
is performed in a water-miscible, inert organic solvent, for example, 
methanol, ethanol, dioxane, and the like in the presence of water. For 
example, such use of sodium hydroxide, sodium carbonate, or sodium 
bicarbonate gives a solution of the sodium salt. Evaporation of the 
solution or addition of a water-miscible solvent of a more moderate 
polarity, for example, a lower alkanol, for instance, butanol, or a lower 
alkanone, for instance, ethyl methyl ketone, gives the solid inorganic 
salt if that form is desired. 
To produce an amine salt, the acidic compound of formula (I) is dissolved 
in a suitable solvent of either moderate or low polarity, for example, 
ethanol, methanol, ethyl acetate, diethyl ether, and benzene. At least an 
equivalent amount of the amine corresponding to the desired cation is then 
added to that solution. If the resulting salt does not precipitate, it can 
usually be obtained in solid form by addition of a miscible diluent off 
lower polarity, for example, benzene or petroleum ether, or by 
evaporation. If the amine is relatively volatile, any excess can easily be 
removed by evaporation. It is preferred to use essentially equivalent 
amounts of the less volatile amines. 
Salts wherein the cation is quaternary ammonium are produced by mixing the 
acid of formula (I) with an equivalent amount of the corresponding 
quaternary ammonium hydroxide in water solution, followed by evaporation 
of the water. 
The 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids and the 
pharmaceutically acceptable salts thereof of this invention may be 
administered to mammals, for example, man, monkeys, or dogs, either alone 
or combined with pharmaceutically acceptable excipients, in dosage forms, 
i.e., capsules or tablets. 
Preferably, the compounds of this invention may be given orally. However, 
the method of administering the present active ingredients of this 
invention is not to be construed as limited to a particular mode of 
administration. For example, the compounds may be administered topically 
directly in the eye in the form of drops of sterile, buffered ophthalmic 
solutions, preferably of pH 7.2-7.6. Also, they may be administered orally 
in solid form containing such excipients as starch, milk sugar, certain 
types of clay, and so forth. They may also be administered orally in the 
form of solutions or they may be injected parenterally. For parenteral 
administration they may be used in the form of a sterile solution, 
preferably of pH 7.2-7.6, containing a pharmaceutically acceptable buffer. 
The dosage of the 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids 
and the pharmaceutically acceptable salts thereof will vary with the form 
of administration. Furthermore, it will vary with the particular host 
under treatment. Generally, treatment is initiated with small dosages 
substantially less than the optimal dose of the compound. In general, the 
compounds of this invention are most desirably administered at a 
concentration level that will generally afford effective results without 
causing any harmful or deleterious side effects. For topical 
administration, a 0.05-1.8% solution may be administered dropwise in the 
eye. The frequency of instillation varies with the subject under treatment 
from a drop every two or three days to once daily. For oral or parenteral 
administration a preferred level of dosage ranges from about 0.5 mg to 
about 1000 mg per kilo of body weight per day, although aforementioned 
variations will occur. However, a dosage level that is in the range of 
from about 5.0 mg to about 60 mg per kilo of body weight per day is most 
satisfactory. 
Unit dosage forms such as capsules, tablets, pills, and the like may 
contain from about 25 mg to about 1250 mg of the active ingredients of 
this invention with a pharmaceutical carrier. Thus, for oral 
administration, capsules can contain from between about 25 mg to about 
1250 mg of the active ingredients of this invention with or without a 
pharmaceutical diluent. Tablets, either effervescent or noneffervescent, 
can contain between about 25 to 1250 mg of the active ingredients of this 
invention together with conventional pharmaceutical carriers. Thus, 
tablets, which may be coated and either effervescent or noneffervescent, 
may be prepared according to the known art. Inert diluents or carriers, 
for example, magnesium carbonate or lactose, can be used together with 
conventional disintegrating agents, for example, starch. 
The 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids and the 
pharmaceutically acceptable salts thereof can also be used in combination 
with insulin or oral hypoglycemic agents to produce a beneficial effect in 
the treatment of diabetes mellitus. In this instance, commercially 
available insulin preparations or oral hypoglycemic agents, exemplified by 
acetohexamide, chlorpropamide, tolazamide, tolbutamide, and phenformin, 
are suitable. The compounds herein can be administered sequentially or 
simultaneously with insulin or the oral hypoglycemic agent. Suitable 
methods of administration, compositions, and doses of the insulin 
preparation or oral hypoglycemic agent are described in medical textbooks; 
for instance, "Physicians' Desk Reference", 36 ed., Medical Economics Co., 
Oradell, N.J. U.S.A., 1982. When used in combination, the 
2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids and the 
pharmaceutically acceptable salts thereof are administered as described 
previously. The 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids and 
the pharmaceutically acceptable salts thereof can be administered with an 
oral hypoglycemic agent in the form of a pharmaceutical composition 
comprising effective amounts of each agent. 
The aldose reductase inhibiting property of the compounds of this invention 
and the utilization of the compounds in preventing, diminishing, and 
alleviating diabetic complications are demonstrable in experiments using 
galactosemic rats, see Dvornik et al, Science, 182, 1146 (1973). Such 
experiments are exemplified hereinbelow after the listing of the following 
general comments pertaining to these experiments. 
Male Sprague-Dawley rats, weighing approximately 90 grams were separated 
into groups of equal average body weight, with six animals per group. The 
animals were housed in cages of six animals each and maintained on 12 hour 
night/12 hour day cycles. Except as otherwise noted, the animals were 
given food and water ad libitum. 
On day 1, the galactosemic control group and all drug-treated groups were 
given access to 20% galactose chow (Bio-Serv, Frenchtown, NJ). Animals in 
the control group were given access to 20% glucose chow (Bio-Serv). Test 
compounds were administered either in the diet or by gavage as a 
suspension in 2% Tween 80 in saline. In experiments in which gavage dosing 
was used, the animals were administered the test compound daily at 
approximately the same hour each day. Food intake and body weight were 
determined twice during the course of the experiment. In cases in which 
the compound was administered in the diet, the average dose was calculated 
on the basis of the actual average food intake during the experiment. 
On the morning of day 5, all animals were fasted; beginning two hours later 
the animals were decapitated and the lenses, sciatic nerves, and a 50-100 
mg portion of the diaphragm were removed, weighed, and frozen in porcelain 
plates on dry ice. 
The polyol determination was performed by a modification of the procedure 
of M. Kraml et al, Clin. Biochem., 2, 373 (1969). Only two minor reagent 
changes were made: (a) the rinsing mixture was an aqueous 5% (w/v) 
trichloroacetic acid solution and (b) the stock solution was prepared by 
dissolving 25 mg of dulcitol in 100 mL of an aqueous trichloroacetic acid 
solution. [N.B.: For each experiment the average value found in the tissue 
from rats fed the glucose diet was subtracted from the individual values 
found in the corresponding tissue in galactose-fed rats to obtain the 
amount of polyol accumulated.] 
The aldose reductase inhibiting effects of the compounds of formula (I) 
were also tested by employing an in vitro testing procedure similar to 
that described by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240, 877 
(1965). In the present case the procedure of Hayman and Kinoshita was 
modified in that the final chromatography step was omitted in the 
preparation of the enzyme from bovine lens. 
The following tabulated results show that the 
2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids of this invention 
show the property that they diminish the accumulation of galactitol in the 
lenses and sciatic nerves of rats fed galactose. The figures under L, N 
and D represent the percentage decrease of galactitol accumulation in the 
tissues of the lens, sciatic nerve, and diaphragm, respectively, for 
treated rats as compared to untreated rats. 
The last entry in the tables is the compound 
N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-thioxomethyl]-N-methylgl 
ycine. The latter compound is also known as tolrestat. (See U.S. Pat. No. 
4,568,693.) 
TABLE 1 
__________________________________________________________________________ 
##STR2## (I) 
Test % Inhibition % Lowering dulcitol 
Compound IN VITRO accumulation IN 
Melting 
Example No. 
R.sup.1 R 10.sup.-5 M 
10.sup.-6 M 
10.sup.-7 M 
mg/kg 
L N D Point 
__________________________________________________________________________ 
.degree.C. 
1 t-butyl 
##STR3## 97 96 88 105 -- 70 60 
126-128 
2 t-butyl 
##STR4## 98 93 93 99 -- 28 47 
154-155 
3 t-butyl SCH.sub.3 89 88 82 83 -- 35 32 
212-215 
4 t-butyl-CH.sub.2 
SCH.sub.3 95 96 85 98 -- -- 22 
155-157 
5 i-propyl SCH.sub.3 98 97 88 78 -- 37 -- 
158-160 
##STR5## SCH.sub.3 91 90 78 76 -- -- -- 
171-173 
7 n-propyl SCH.sub.3 92 89 74 78 -- -- -- 
160-162 
8 
##STR6## 
##STR7## 95 91 73 117 -- -- -- 
182-183 
9 
##STR8## SCH.sub.3 95 93 82 114 -- -- 27 
233-235 
10 t-butyl 
##STR9## 95 95 95 135 -- -- 58 
160-162 
11 t-butyl SnC.sub.6 H.sub.13 
94 94 91 112 -- 43 60 
91-92 
12 t-butyl Si-propyl 92 91 89 82 -- 37 19 
120-122 
13 CH.sub.3 SCH.sub.3 90 84 55 79 -- -- -- 
205-206 
14 
##STR10## 
SCH.sub.3 92 87 75 96 -- -- 55 
223-224 
15 
##STR11## 
SCH.sub.3 90 90 74 91 -- -- -- 
149-150 
16 t-butyl 
##STR12## 86 85 82 97 -- 46 67 
126-129 
17 
##STR13## 
SCH.sub.3 98 97 92 90 -- -- -- 
211-215 
__________________________________________________________________________ 
The compounds of Table 1 are produced by Process 1 set forth below. 
TABLE 2 
__________________________________________________________________________ 
##STR14## (I) 
% Inhibition % Lowering dulcitol 
Test Compound IN VITRO accumulation IN 
Melting 
Example No. 
R.sup.1 R 10.sup.-5 M 
10.sup.-6 M 
10.sup.-7 M 
mg/kg 
L N D Point 
__________________________________________________________________________ 
.degree.C. 
1 5-Brnaphthalenyl 
1-naphthalenylmethyl 
90 85 46 166 -- -- 
-- 236-237(dec.) 
##STR15## 
CH.sub.3 92 88 79 78 -- -- 
-- 228-229 
3 1-naphthyl 
CH.sub.3 93 85 46 83 -- -- 
-- 198-199 
4 
##STR16## 
##STR17## 96 94 85 100 17 -- 
-- 221-222 
5 1-naphthalenyl 
##STR18## 79 76 53 112 -- -- 
-- 187-188 
6 5-Brnaphthalenyl 
i-propyl 94 90 53 120 -- -- 
-- 209.5-210.5 
N[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- - 
98 94 65 6 N.S. 
53 
90 164-165 
thioxomethyl] -Nmethylglycine(tolrestat) 
U.S. Pat. No. 4,568,693 
__________________________________________________________________________ 
The compounds of Table 2 are produced by Process 2 set forth below. 
N.S. = not significant? 
THE PROCESS 
The 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acids of the present 
invention were produced by Process 1, condensation of suitable amidines 
(III) with .beta.,.beta.-bisthioalkyl-.alpha.-cyanoacrylic acid methyl 
esters (VI) to produce pyrimidines (VII); and Process 2, condensation of 
cyanoacetamide (XIV) with N-acyliminoethers (XIII) to produce the 
pyrimidines (XV). O-Alkylations of (VII) and (XV) were carried out with 
X--CH.sub.2 COOR.sup.4 wherein R.sup.4 is lower alkyl, and X is bromine or 
iodine; preferably with methyl or t-butyl bromoacetates to produce the 
pyrimidine esters (VIII) and (XVI); and finally hydrolysis of (VIII) and 
(XVI) to the desired compounds of formula (I). 
##STR19## 
wherein R.sup.1 and R.sup.2 are as defined above; R.sup.4 is lower alkyl 
containing 1 to 4 carbon atoms; and X is bromine, or iodine. 
##STR20## 
wherein R.sup.1, R.sup.3, R.sup.4, and X are as defined above. 
Referring to Process 1, the required amidines (III) were obtained from the 
corresponding nitriles (II) in two steps via iminoethers as described in 
P. E. Fanta et al, J. Am. Chem. Soc., 78, 1434 (1956). However, 
preparation of naphthalenyl amidine as reported in L. Weintraub, J. Org. 
Chem., 33, 1679 (1968), via the iminoether of naphthalenyl-1-carboxamide 
was not reproducible in our hands. The reaction yielded either the 
starting material or naphthalenyl-1-carbonitrile. The naphthalene moiety 
was introduced using the alternative synthesis described in Process 2. The 
required .beta.,.beta.-bisthioalkyl-.alpha.-cyanoacrylic acid methyl 
esters (VI) in Process 1 were prepared using the general process reported 
in K. A. Jensen et al, Acta Chem. Scand., 22, 1107 (1968), for the 
reaction of carbon disulfide with active methylene containing compounds 
(IV) to produce the compounds (V), followed by alkylation. 
Referring to Process 2, the nitriles (X) were transformed to the 
corresponding iminoethers (XI). Condensation of these iminoethers (XI) 
with an acyl chloride (XII) led to the N-acylimidates (XIII). These 
compounds, on condensation with cyanoacetamide (XIV), according to J. L. 
Soto et al, J. Chem. Soc. Perkins Trans I., 2447 (1984), led to suitably 
substituted pyrimidines (XV). 
In both Process 1 and 2, alkylation of pyrimidines (VII) and (XV), 
respectively, was effected using sodium hydride as a base in the presence 
of suitable solvents. It was observed that the proportion of N- and 
O-alkylated products can be controlled by the choice of the solvent used 
for the reaction. Thus, using tetrahydrofuran (THF), or dimethoxyethane 
(DME), it was possible to preferentially obtain N-alkylation, whereas use 
of dimethylformamide (DMF) as a solvent led to O-alkylation as a 
preponderant product. 
The alkylation could be affected either by using methyl bromoacetate or 
t-butyl bromoacetate. 
The structures of the products of formula (I) was assigned based on the 
following observations. 
(1) The infrared spectra showed only one carbonyl absorption band at 
1720-1740 cm.sup.-1 due to the carboxylic acid carbonyl. 
(2) The --O--CH.sub.2 --signal characteristic in the NMR. 
(3) The higher R.sub.f on the thin layer chromatography relative to the 
N-alkylated isomers. 
The following Examples further illustrate this invention. 
EXAMPLE 1 
(Process 1) 
[[5-Cyano-6-[(cyclohexylmethyl)thio]-2-(1,1-dimethylethyl)-4-pyrimidinyl]ox 
y]acetic Acid 
[(I): R.sup.1 =t-butyl; R=(cyclohexylmethyl)thio] 
Step (1) Preparation of t-Butyl Amidine Hydrochloride 
To a cooled (0.degree. C.), magnetically stirred solution of 
2,2-dimethyl-1-propanenitrile (25.0 g, 0.30 mol), dry methanol (26.8 mL, 
0.79 mol), and ether (30 mL) was added acetyl chloride (25.7 mL, 0.36 mol) 
dropwise. After the addition, cooling was continued for 15 minutes. The 
mixture was stirred at room temperature for 3 days. The resulting white 
crystals were filtered, washed with ether, and dried in vacuo. After 
drying, the crystals were combined with 10% NH.sub.3 /ethanol (150 mL, 
0.90 mol), and stirred at room temperature for 3 days. The solution was 
filtered, and the filtrate was concentrated to give a white solid. 
Recrystallization from ethanol yielded white crystals (18.9 g, 46%), m.p. 
188.degree.-190.degree. C. 
NMR (DMSO-d.sub.6): .delta.1.22 (s, 9H), 8.63 (br d, 3H). 
Step (2) Preparation of Methyl 3,3-Dithio-2-cyano-2-propenoate Dipotassium 
Salt 
According to the procedure of K. A. Jensen et al, Acta Chem. Scand., 22, 
1107 (1968), to a cooled (20.degree. C.), stirred suspension of powdered 
KOH (10.0 g, 0.18 mol) in dioxane (50 mL) was added a solution of methyl 
cyanoacetate (7.9 mL, 0.09 mol), and carbon disulfide (5.4 mL, 0.09 mol) 
in dioxane (30 mL) dropwise over 30 minutes. The cooling bath was removed 
and stirring was continued for 1 hour. Ether (75 mL) was added and the 
reaction mixture was filtered. The collected solid was washed with 1:1 
dioxane/ether (100 mL), and dried over P.sub.2 O.sub.5 in vacuo to yield a 
yellow powder (15.7 g, 70%). The product was used without further 
purification. 
NMR (DMSO-d.sub.6): .delta.4.15 (s, 3H). 
Step (3) Preparation of Methyl 
3,3-Bis(cyclohexylmethylthio)-2-cyano-2-propenoate 
To a stirred solution of methyl 3,3-dithio-2-cyano-2-propenoate dipotassium 
salt (17.8 g, 0.07 mol) in water (50 mL) was added a solution of 
bromomethylcyclohexane (19.8 mL, 0.14 mol) in ethanol (100 mL). The 
resulting solution was heated at reflux for 5 hours, concentrated, and 
diluted with water. The mixture was extracted with ethyl acetate, and the 
combined extracts were dried (MgSO.sub.4) and concentrated. Purification 
of the crude product by flash column chromatography (eluant, 5% ethyl 
acetate/hexane) gave a yellow oil (16.4 g, 63%). 
NMR (DMSO-d.sub.6): .delta.1.33 (m, 22H), 3.20 (t, 4H), 3.75 (s, 3H). 
Step (4) Preparation of 
4-[(Cyclohexylmethyl)thio]-1,6-dihydro-2-(1,1-dimethylethyl)-6-oxo-5-pyrim 
idinecarbonitrile 
To a cooled (0.degree. C.), stirred suspension of NaH (50% dispersion in 
mineral oil, washed with hexane, 1.49 g, 0.030 mol) in DMF (8 mL) was 
added a solution of t-butyl amidine (prepared in Step 1) (3.35 g, 0.025 
mol) in DMF (10 mL) dropwise. The mixture was stirred at room temperature 
for 1 hour and then recooled to 0.degree. C. A solution of methyl 
3,3-bis(cyclohexylmethylthio)-2-cyano-2-propenoate (prepared in Step 3) 
(8.20 g, 0.022 mol) in DMF (25 mL) was added dropwise. The resulting 
solution was stirred at room temperature overnight. Water (100 mL) was 
added, the solution was filtered, and the filtrate was acidified with 
concentrated Hcl (10 mL). A precipitate formed and was collected by 
filtration. Trituration with acetone yielded an off-white powder (4.80 g, 
71%), which was used withut further purification. 
NMR (DMSO-d.sub.6): 1.30 (s, 9H), 1.38 (m, 11H), 3.15 (d, 2H). 
Step (5) Preparation of t-butyl 
[[5-Cyano-6-[(cyclohexylmlethyl)thio]-2-(1,1-dimethylethyl)-4-pyrimidinyl] 
oxy]acetate 
To a cooled (0.degree. C.), stirred suspension of NaH (50% dispersion in 
mineral oil, washed with hexane, 0.91 g, 0.019 mol) in DMF (10 mL) was 
added a solution of 
4-[(cyclohexylmethyl)thio]-1,6-dihydro-2-(1,1-dimethylethyl)-6-oxo-5-pyrim 
idinecarbonitrile (prepared in Step 4) (4.80 g, 0.016 mol) in DMF (70 mL) 
dropwise. The mixture was stirred at room temperature for one hour. 
t-Butyl bromoacetate (3.05 mL, 0.019 mol) was added and stirring was 
continued overnight. Water (150 mL) was added, and the resulting 
precipitate was collected by filtration to give a white solid (6.05 g, 
92%). The product was used without further purification. 
NMR (CDCl.sub.3): .delta.1.29 (s, 9H), 1.38 (m, 11H), 1.45 (s, 9H), 3.20 
(d, 2H), 4.85 (s, 2H). 
Step (6) Preparation of 
[[5-Cyano-6-[(cyclohexylmethyl)thio]-2-(1,1-dimethylethyl)-4-pyrimidinyl]o 
xy]acetic Acid 
A solution of t-butyl 
[[5-cyano-6-[(cyclohexylmethyl)thio]-2-(1,1-dimethylethyl)-4-pyrimidinyl]o 
xy]acetate (prepared in Step 5) (6.05 g, 0.014 mol) in trifluoroacetic acid 
(40 mL) was stirred at room temperature for 3 hours. The reaction mixture 
was concentrated to give a brown gum. Recrystallization from acetonitrile 
(3 times) yielded a white powder (2.1 g, 40%), m.p. 
126.degree.-128.degree. C. 
NMR (CDCl.sub.3): .delta.1.30 (s, 9H), 1.40 (m, 11H), 3.16 (d, 2H), 4.98 
(s, 2H). 
IR (KBr): 2220, 1740 cm.sup.-1. 
UV (CH.sub.3 OH): 238 (29,600), 270 (10,000). 
MS (m/e): 363, 224 (100%), 83. 
Anal. Calcd.: C, 59.48; H, 6.93; N, 11.56%; Found: C, 59.57; H, 6.85; N, 
11.50%. 
EXAMPLE 2 
(Process 2) 
[[2-(5-Bromo-1-naphthalenyl)-5-cyano-6-[(1-naphthalenyl)methyl]-4-pyrimidin 
yl]oxy]acetic Acid 
[(I): R.sup.1 =5-bromo-1-naphthalenyl; R=(1-naphthalenyl)methyl] 
Step (1) Preparation of Methyl-2-(1-naphthalenyl)acetimidate Hydrochloride 
To a cooled (0.degree. C.), stirred mixture of 1-naphthylacetonitrile (9.2 
g, 0.055 mol), methanol (5.0 mL, 0.124 mol), and ether (5 mL) was added 
acetyl chloride (5.2 g, 0.066 mol) dropwise. Stirring was continued for 30 
minutes and the mixture was allowed to stand at room temperature for 60 
hours. The resulting precipitate was collected by filtration, washed with 
ether, crushed with a mortar and pestle, and again washed with ether. The 
product was dried in vacuo to give a white crystalline solid (11.7 g, 
91%), which was used without further purification. 
NMR (CDCl.sub.3): .delta.4.22 (s, 3H), 4.58 (s, 2H), 7.53 (m, 4H), 7.88 (t, 
2H, J=6.0 Hz), 8.12 (d, 1H, J=7.0 Hz), 11.95 (br s, 1H). 
Step (2) Preparation of 
Methyl-N-(5-bromo-1-naphthoyl)-2-(1-naphthalenyl)acetimidate 
According to the procedure of Soto et al, Synthesis, 483, (1983), to a 
stirred suspension of methyl-2-(1-naphthalenyl)acetimidate hydrochloride 
(prepared in Step 1) (11.7 g, 0.050 mol), in dry toluene (150 mL) was 
added triethylamine (11.5 g, 0.114 mol). 5-Bromo-1-naphthoyl chloride 
(13.4 g, 0.050 mol) was added in one portion and the resulting mixture was 
stirred at room temperature for 16 hours. The precipitated salt was 
removed by filtration and washed with toluene. The filtrate was 
concentrated in vacuo to give an orange oil (21.5 g, 100%) which was used 
without purification. 
NMR (CDCl.sub.3): .delta.3.88 (s, 3H), 4.27 (s, 2H), 7.12 (dd, 1H, J.sub.1 
=12.0 Hz, J.sub.2 =6.0 Hz), 7.30 (m, 5H), 7.48 (d, 1H, J=7.0 Hz), 7.69 (d, 
1H, J=6.0 Hz), 7.87 (m, 3H), 8.36 (d, 1H, J=7.0 Hz), 9.02 (d, 1H, J=7.0 
Hz). 
Step (3) Preparation of 
2-(5-Bromo-1-naphthalenyl)-1,6-dihydro-4-[(1-naphthalenyl)methyl]-6-oxo-5- 
pyrimidinecarbonitrile 
To a stirred solution of sodium methoxide, freshly prepared from sodium 
(1.5 g, 0.065 mol) in methanol (75 mL), was added cyanoacetamide (4.2 g, 
0.050 mol). After 2 minutes, 
methyl-N-(5-bromo-1-naphthoyl)-2-(1-naphthalenyl)acetimidate (21.6 g, 
0.050 mol) was added. The resulting mixture was stirred at room 
temperature for 15 hours, then heated to reflux for 4 hours. After cooling 
to room temperature, the mixture was neutralized with H.sub.2 SO.sub.4 
(1.8 mL) and diluted with water. The product was collected by filtration, 
washed with water, and dried in vacuo to give a yellow solid (16.4 g, 
71%), which was used without purification. 
NMR (DMSO-d.sub.6): .delta.4.63 (s, 2H), 7.07 (t, 1H, J=6.0 Hz), 7.51 (m, 
4H), 7.80 (m, 5H), 7.97 (dd, 1H, J.sub.1 =6.0 Hz, J.sub.2 =2.0 Hz), 8.15 
(dd, 1H, J.sub.1 =8.0 Hz, J.sub.2 =2.0 Hz), 8.34 (d, 1H, J=7.0 Hz). 
Step (4) Preparation of t-Butyl 
[[2-(5-Bromo-1-naphthalenyl)-5-cyano-6-[(1-naphthalenyl)methyl]-4-pyrimidi 
nyl]oxy]acetate 
To a stirred suspension of NaH (60% suspension in mineral oil, washed with 
hexane, 0.64 g, 16.1 mmol) in DMF (25 mL) was added a solution of 
2-(5-bromo-1-naphthalenyl)-1,6-dihydro-4-[(1-naphthalenyl)methyl]-6-oxo-5- 
pyrimidinecarbonitrile (prepared in Step 3) (5.0 g, 10.7 mmol) in DMF (100 
mL) at room temperature. After 30 minutes, t-butyl bromoacetate was added 
and stirring was continued for 18 hours. The reaction was quenched by the 
addition of water (10 mL) and the resulting mixture was partitioned 
between chloroform (200 mL) and water. The aqueous layer was extracted 
with chloroform (2.times.100 mL) and the combined organic layers were 
washed with water, brine, and dried (Na.sub.2 SO.sub.4). The mixture was 
filtered through a short plug of Florosil and concentrated in vacuo to 
give a yellow solid (5.8 g, 48%). Recrystallization from acetonitrile/DMF 
gave 3.0 g of product which was used without further purification. 
NMR (CDCl.sub.3): .delta.1.42 (s, 9H), 4.84 (s, 2H), 5.00 (s, 2H), 6.95 
(dd, 1H, J.sub.1 =J.sub.2 =7.0 Hz), 7.57 (m, 5H), 7.76 (d, 1H, J=6.0 Hz), 
7.90 (m, 2H), 8.20 (m, 3H), 8.43 (d, 1H, J=8.0 Hz). 
Step (5) Preparation of 
[[2-(5-Bromo-1-naphthalenyl)-5-cyano-6-[(1-naphthalenyl)methyl]-4-pyrimidi 
nyl]oxy]acetic Acid 
A solution of t-butyl 
[[2-(5-bromo-1-naphthalenyl)-5-cyano-6-[(1-naphthalenyl)methyl]-4-pyrimidi 
nyl]oxy]acetate (2.7 g, 4.6 mmol) in trifluoroacetic acid (40 mL) was 
stirred at room temperature for 6 hours. The solvent was removed in vacuo 
and the residue was triturated with ether. Recrystallization from ethanol 
(2 times) gave a white solid (1.4 g, 60%), m.p. 236.degree.-237.degree. C. 
NMR (DMSO-d.sub.6): .delta.4.89 (s, 2H), 5.16 (s, 2H), 7.05 (t, 1H, J=7.9 
Hz), 7.52 (m, 4H), 7.73 (t, 1H, J=7.9 Hz), 7.86 (d, 1H, J=7.4 Hz), 7.90 
(d, 1H, J=7.3 Hz), 7.97 (dd, 1H, J.sub.1 =6.9 Hz, J.sub.2 =2.3 Hz), 8.11 
(d, 1H, J=7.3 Hz), 8.19 (d, 1H, J=8.7 Hz), 8.24 (d, 1H, J=8.7 Hz), 8.33 
(d, 1H, J=8.4 Hz), 9.72 (br s, 1H). 
IR (KBr): 3420, 2220, 1730 cm.sup.-1. 
Anal. Calcd.: C, 64.13; H, 3.46; N, 8.01%; Found: C, 64.09; H, 3.34; N, 
8.06%.