5-PYRIMIDINECARBOXAMIDES AND TREATMENT OF LEUKEMIA AND TUMORS THEREWITH

5-PYRIMIDINECARBOXAMIDES; TRAITEMENT DE LA LEUCEMIE ET DES TUMEURS A L'AIDE DE CES COMPOSES

English Abstract

Case 5993 KON 1A
ABSTRACT
Novel 5-pyimidinecarboxamides useful for
regressing or inhibiting the growth of leukemia and tumors
in mammals. The compounds have the formula:
<IMG>
wherein:
R is hydrogen, 2- or 3- halo, 4-fluoro,
2-methyl, 4-(C1-C6 alkoxyl), 4-trifluoromethyl, or
hydroxyl, and R1 is hydrogen; or
R is 2-fluoro and R1 is 4-fluoro; or
R is 2-methoxy and R1 is 5-methyl; and
R2 and R3 are hydrogen atoms or carbohydrate
residues; and
the pharmacologically acceptable acid -
addition salts thereof.

Claims

-39-
CLAIMS
1. A process for the production of a compound of the
formula:
<IMG>
wherein
R is hydrogen, 2- or 3-halo, 2-methyl,
4-fluoro, 2- or 4-alkoxy having from 1 to 6 carbon atoms, 2- or
4-trifluoromethyl, and R1 is hydrogen; or
R is 2-fluoro and R1 is 4-fluoro; or
R is 2-methoxy and R1 is 5 methyl;
and
R2 and R3 are hydrogen atoms or
carbohydrate residues; and,
with the exception of the compound
wherein R is 4-methoxy and R1 is hydrogen, the
pharmacologically acceptable acid addition salts thereof,
which process comprises a process chosen from the group
consisting of
(a) reacting a 2-thiobarbituric acid compound:
<IMG>

-40-
with a phenylisocyanate
<IMG>
in the presence of a solvent or dispersing medium;
(b) reacting a thiourea of formula <IMG> with an
arylaminocarbonylpropanedioic acid diester
<IMG>
wherein R7 is lower alkyl;
(c) reacting an S-substituted pseudo thiourea
<IMG>

-41-
wherein R' is lower alkyl,with an arylaminocarbonylpropanedioic
acid diester
<IMG>
to form the corresponding 2-substituted thiopyrimidinyl
compound:
<IMG>
wherein R' is lower alkyl, and
reacting the 2-substituted thiopyrimidinyl compound with
hydrogen sulfide or an alkali metal or ammonium salt thereof:
(d) alkylating a compound of the formula:
<IMG>
to produce a 2-(alkylthio)-substituted compound of the formula
<IMG>

-42-
reacting the resulting product with a phenylisocyanate
<IMG>
to form a compound incorporating the desired 5-carboxamido
moiety, having the formula:
<IMG>
;and
reacting the compound thus formed with hydrogen sulfide
or an alkali metal or ammonium salt thereof; and
(e) reacting the corresponding 2-aminopyrimidinecarboxamide:
<IMG>

-43-
with hydrogen sulfide or an alkali metal or ammonlum salt
thereof to displace the amino group therefrom.
2. A compound of the formula
<IMG>
wherein:
R is hydrogen, 2- or 3-halo, 2-methyl,
4-fluoro, 2- or 4-alkoxy having from 1 to 6 carbon atoms, 2 or
4-trifluoromethyl, and R1 is hydrogen; or
R is 2-fluoro and R1 is 4-fluoro; or
R is 2-methoxy and R1 is 5-methyl;
and
R2 and R3 are hydrogen atoms or
carbohydrate residues; and, with the exception of the compound
wherein R is 4-methoxy and R1 is hydrogen,the
pharmacologically acceptable acid addition salts thereof .

-44-
3. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 2 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
4. The process as in Claim 1, wherein R is hydrogen or a
2-chloro, 2-methyl, 3-fluoro, 4-fluoro, 4-methoxy or a 4-ethoxy
group.
5. A compound of the formula
<IMG>
wherein:
R is hydrogen or a 2-chloro, 2-methyl, 3-fluoro,
4-fluoro, 4-methoxy or a 4-ethoxy group, and Re is hydrogen;
and
R2 and R3 are hydrogen atoms or carbohydrate
residues; and,
with the exception of the compound wherein R is 4-methoxy
and R1 is hydrogen, the pharmacologically acceptable
acid-addition salts thereof.

-45-
6. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 5 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
7. The process as in Claim 1 for preparing
1,2,3,4-Tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-
pyrimidinecarboxamide.
8. 1,2,3,4-Tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-
thioxo-5-pyrimidinecarboxamide.
9. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 8 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
10. The process as in Claim 1 for preparing N-(2-Chloro-
phenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-
5-pyrimidinecarboxamide.
11. N-(2-Chlorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4
oxo-2-thioxo-5-pyrimidinecarboxamide.

-46-
12. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 11 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
13. The process as in Claim 1 for preparing 1,2,3,4-
Tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-2-thioxo 5-pyrimi-
dinecarboxamide.
14. 1,2,3,4-Tetrahydro-6-hydroxy-N-(2-methylphenyl)-
-4-oxo-2-thioxo-5-pyrimidinecarboxamide.
15. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 14 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
16. The process as in Claim 1 for preparing
N-(3-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
17. N-(3-Fluorophenyl)-1,2,3,4 tetrahydro-6-hydroxy 4-
oxo-2-thioxo-5-pyrimidinecarboxamide,

-47-
18. A pharmaceuticsl composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 17 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
19. The process as in Claim 1 for preparing
N-(4-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
20. N-(4-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-
oxo-2-thioxo-5-pyrimidinecarboxamide.
21. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 20 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
22. The process as in Claim 1 for preparing
1,2,3,4-Tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-oxo-
2-thioxo-5-pyrimidinecarboxamide.
23. 1,2,3,4-Tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-
oxo-2-thioxo-5-pyrimidinecarboxamide.

-48-
24. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 23 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
25. The process as in Claim 1 for preparing N-(4-
Ethoxyphenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-
pyrimidinecarboxamide.
26. N-(4-Ethoxyphenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-
oxo-2-thioxo-5-pyrimidinecarboxamide.
27. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 26 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
28. The process as in Claim 1 for preparing
N (2-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
29. N-(2-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-
oxo-2-thioxo-5-pyrimidinecarboxamide.

-49-
30. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors in mammals,
which comprises a therapeutically effective amount of the
compound of Claim 29 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
31. The process as in Claim 1 for preparing
N-(2,4-Difluorophenyl)-1,2,3,4-tetrahydro-6 hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
32. N-(2,4-Difluorophenyl) 1,2,3,4-tetrahydro-
6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide.
33. A pharmaceutical composition gor inducing regression
of leukemia and inhibition of the qrowth of tumors is mammals,
which comprises a therapeutically effective amount of the
compound of Claim 32 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
34. The process as in Claim 1 for preparing
1,2,3,4-Tetrahydro-6-hydroxy-N-(2-methoxy-5-methyl-phenyl)-
4-oxo-2-thioxo-5-pyrimidinecarboxamide.
35. 1,2,3,4-Tetrahydro-6-hydroxy-N-(2-methoxy-5-phenyl)-
-4-oxo-2-thioxo-5-pyrimidinecarboxamide.

-50-
36. A pharmaceutical composition for inducing regression
of leukemia and inhibition of the growth of tumors mammals,
which comprises a therapeutically effective amount of the
compound of Claim 35 in admixture with a pharmaceutically
acceptable, substantially nontoxic carrier or excipient.
37. A process for the production of a compound of the
formula:
<IMG>
wherein
R is hydrogen, 2- or 3-halo, 2-methyl,
4-fluoro, 2-or 4-alkoxy having from 1 to 6 carbon atoms, 2 or
4-trifluoromethyl, and R1 is hydrogen; or
R is 2-fluoro and R1 is 4-fluoro; or
R is 2-methoxy and R1 is 5-methyl:
and
R2 and R3 are hydrogen atoms or
carbohydrate residues: and,
with the exception of the compound
wherein R is 4-methoxy and R1 is hydrogen, the
pharmacologically acceptable acid addition salts thereof,

-51-
which process comprises reacting a 2-thiobarbituric acid
compound:
<IMG>
with a phenylisocyanate
<IMG>
in the presence of a solvent or dispersing medium.
38. The process as in Claim 37, wherein R is hydrogen or
a 2-chloro, 2 methyl, 3-fluoro, 4-fluoro, 4-methoxy or a
4-ethoxy group.
39. The process as in Claim 37 for preparing
1,2,3,4-Tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-
pyrimidinecarboxamide.
40. The process as in Claim 37 for preparing N-(2-Chloro-
phenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-
pyrimidinecarboxamide.

-52-
41. The process as in Claim 37 for preparing
1,2,3,4-Tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-2-thioxo-
5-pyrimidinenecarboxamide.
42. The process as in Claim 37 for preparing
N-(3-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
43. The process as in Claim 37 for preparing
N-(4-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
44. The process as in Claim 37 for preparing
1,2,3,4 Tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-oxo-
2-thioxo-5-pyrimidinecarboxamide.
45. The process as in Claim 37 for preparing N-(4-
Ethoxyphenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-
pyrimidinecarboxamide.
46. The process as in Claim 37 for preparing
N-(2-Fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
thioxo-5-pyrimidinecarboxamide.
47. The process as in Claim 37 for preparing
N-(2,4-Difluorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thi-
oxo-5-pyrimidinecarboxamide.
48. The process as in Claim 37 for preparing
1,2,3,4-tetrahydro-6-hydroxy-N-(2-methoxy-5-methylphenyl)-
4-oxo-2-thioxo-5-pyrimidinecarboxamide.

Description

12~ D~ case 5993 KON lA
1 5-PYRIMIDINECARBOXAMIDES AND TREATMEN~ OF
LEUKEMIA AND TUMORS THEREWITH
Technic~l Fi-1~3
s
This invention relates to new 5-pyrimidine-
carboxamides, and the pharmacologically acceptable addi-
tion salts and nucleosides thereof. ~ore particularly,
the invention relates to new 5-pyrimidinecarboxamide
10 derivatives which have anti-leukem;ia and anti-tumor
activity, to pharmaceutical compositions containing such
derivative~ as the therapeutically effective constituents
thereof, and to a method utilizing the same for inducing
the regression of leukemia and/or the inhibition of growth
of tumors in mammals.

--3--
1 Back~lround Art
5-pyrimidinecarboxamides, and particularly 5-
carboxamides of barbituric acid, have previously been
described as potential anti-cancer agents D Thus, Takeda
Pharmaceutical Industries' Japanese Patent Publication
No. 1,445/64, published on February 14, 1964, suggests the
use of compounds of the formula:
(I) ~ ON
R
i.e., 5-phenylcarbamoylbarbituric ~cid (whereln R ls
hydrogen) and l-substltuted-phenylcarbamoylbarbiturlc
aclds (wherein R is alkyl or phenyl), for such purpose.
20 When subjected to ln vivo testing on Ehrlich Ascites car-
cinoma in mice the unsubstituted compound, but neither of
its l-methyl or l-phenyl-substituted derivatives,
exhibited anti-tumor activity. Chem. ~ Pharm. Bull.
~Tokyo) 8, 1021-1028 (1960~.
Analogs of similar barbituric acid derivatives
have also been described in the literature. Thus, N-sub-
stituted-2-amidocarbonylthiobarbituric acids of the
formula:
O
Il X
R2_~ ~ C - N~ R
(II3 ~ ~ H
R~

-4-
1 wherein Rl is alkyl, alkenyl, various substituted alkyl,
alkenyl or carbonyl, or optionally substituted aryl or
aralkyl, R2 and R3 each independen~ly is alkyl, alkenyl,
cycloalkyl, aryl, aralkyl or hydrogen, provided that not
more than one of R2 and R3 is hydrocJen, and X is oxygen or
~ulfur, are di~closed in Bayer AG German Offen. 24 05 732
and in Kramer et al., U.S. Patent No. 3,961,061 granted on
June 1, 1976. These thiobarbituric acid derivatives are
described as possessing insecticidal, acaricidal,
10 fungicidal and bactericidal properties.
Other 5-carboxamido-substituted thiobarbituric
acids such as:
~ ~3
R ~ C
~III) OH
~2
wherein X is oxygen or sulfur, Rl and R2 may each be
alkyl, alkenyl, benzyl or unsubstituted or s~bstituted
phenyl, R3 may be halogen, nitro or trihalomethyl, R4 is
hydrogen, halogen or trihalomethyl, and ~5 is hydrogen,
halogen, methyl or methoxy, are also described in the
patent literature. Such compounds are disclosed in
Ciba-Geigy European Patent Publication No. 74,335 and in
De Sousa et al~, V.S. Patent No. 4l283,444 granted on
August 11, 1981, as useful for protecting keratinous mate-
rial, especially wool, from insect attack.
It is among the objects of the present invention
to provide a new class of 5-pyrimidinecarboxamides, in
particular a new group of 5-carboxamide-2-thiobarbituric
acid derivatives, which are useful anti-leukemia and anti-
tumor agents, as well as pharmaceutical compositions and
therapeutic methods for utilizing the same. Other objects
and advantages of the invention will be apparent from the

~2~;6~
~ - 5 -
following detailed description of preferred embodiments
th~ r eof .

~'~S6~
--6--
1 Summary of the Invention
The novel 5-pyrimidinecarboxamides of the pre-
sert invention are 5-carboxamide 2-thiobarbituric acid
derivatives of the formula:
lû (;i;V) l~t CON~Rl
~ OH
R2
15 wherein
R is hydrogen, 2 or 3-halo, 2-methyl, 4-fluoro,
4-(Cl-C6 alkoxyl), 2 or 4-trlfluoromethyl, or hydroxyl,
and Rl is hydrogen;
or R is 2-fluoro and ~1 is 4-fluoro;
or R is 2-methoxy and Rl is 5-methyl; and
R2 and R3 are hydrogen atoms or carbohydrate
residues; and the pharmacologically acceptable addi~ion
salts thereof.
When R2 is hydrogen, addition salts may be
formed with a variety of pharmacologically acceptable
organic and invrganic salt-forming reagents. Useful addi-
tion salts may thus be formed by admixture of the organic
acid with one equivalent of a base, e.g., an organic amine
such as triethylamine or N-methyl glucamine, and inorganic
cations such as sodium, potassium or the like. The addi-
tion salts of the organic acids of the invention are, in
general, crystalline solids which are rela~ively insoluble
in both polar solvents such as water, methanol and ethanol
and non-polar organic solvents such as diethyl ether,
benzene, ~oluene and the like~ ~hey are somewhat soluble
in aprotic solvents such as dimethylformamide and
dimethylsulfoxide.

~l256~
1 On the other hand, when R2 is a carbohydrate
residue it may be furano~yl (e.gO, arabinofuranosyl or
ribofuranosyl), pyranosyl (e.g~, arabinopyranosyl,
glucopyranosyl, rhamnopyranosyl, or xylopyranosyl), their
deoxy derivatives, or their aliphatic analogs ~e.g.,
hydroxyalkoxyalkyl or polyhydroxyalkyl groups having from
2 to 12 carbon atoms in each of the alkoxy and alkyl
moieties thereof, such as 2-hydroxyethoxymethyl or 2,3-di-
hydroxypropyl. As used herein, the term ~carbohydrate
10 residuen is intended to refer to those cyclic and acyclic
groups which form pyrimidine nucleosides or the pseudo
nucleosides, e.g., materials including both the cyclic and
acyclic groups specified hereinabove.
The 5-carboxamide-2-thiobarbituric acid
15 derivatives of the invention can exist in the form illus-
trated ln Formula IV or in any of its tautomeric forms.
For ease o~ understandlng, the compounds of the invention
~ill only be illustrated herein in the form shown in
Formula IV but will be understood to embrace the tautomers
thereof, or tautomeric mixtures.
The novel 5-carboxamide-2-thiobarbituric acid
derivatives of the invention may be readily prepared by
reacting 2-thiobarbituric acid with phenylisocyanate or an
appropriate substituted phenylisocyanate, in the presence
of a solvent or dispersing medium such as dimethyl
sulfoxide, pyridine, dimethylformamide, N-methylpyr-
rolidone, dimethylacetamide, sulfolane, tetrahydrothio-
phene oxide, acetonitrile, or a tertiary amine such as
triethylamine. The molar proportions of the 2-thiobarbi-
3~ turic acid to the phenylisocyanate reactant may range fromabout 2:1 to 1:2, and are preferably from about 1.1:1 to
1:1.1, stoichiometric proportions generally sufficing.
The reaction may be carried out at temperatures varying
from about 0 to 200C, usually at from about 24 to 1~0C;
in most cases, the reaction proceeds quite well at temper-
atures of from about 80 to 100C. Formation of the 5-
carboxamide derivatives is substantially complete within
reaction periods varying from about 1/2 to 6, and usually
from ahout 2 to 4, hours.

:L2~6~
--8--
1 Alternatively, the carboxamides may be prepared
by other routes. For example, thiourea may be reacted
with appropria~ely substituted 2-benzoylamino propanedioic
diesters, and the resulting products separa~ed and
5 recovered. O~her syntheses of the 5-carboxamide-2-thio-
barbituric acid deriva~ives will readily occur to those
~ skilled in the art.
The novel compounds of the invention are
cytotoxic agents useful to induce the regression of blood
10 malignancies such as leukemia, as well as to înhibit the
yrowth of solid and non-solid tumors. They may be used
alone or in combination with other chemotherapeutic agents
active for these purposes. As used herein, the terms
nregression~ and ~inhibition" comprehend arresting or
15 retarding the growth of the malignancy or other
manifestatlon of the disease, as compared with the course
of the disease ln the absence of treatment.
Admlnistration of the novel 5-carboxamido-2-
thiobarbituric acid derivatives to mice in amounts ranging
2~ from about 12-~00 mg./kg., preferably from about 25-100
mg./kg., of body weight has been found effective to ind~ce
the regression of leukemia and to inhibit the gro~th of
tumors. The interrelationship of dosages for mammals of
other sizes and species is described by Freireich, E.J.,
25 et al., ~uantitative Comparison of Toxicity of Anti-cancer
Agents in ~ouse, Rat, Hamster, Dog. Monkey and Man, Cancer
Chemotherapy, Reg. 50, No. 4,219-244, May 1966.
The dosage level may, of course, be adjusted to
provide optimum therapeutic response. For example, sev-
30 eral divided doses may be administered daily, or the dosemay be proportionally reduced, as indicated ky the exigen-
cies of the therapeutic situation.
~ he active compounds may suitably be adminis-
tered parenterally, intraperitoneally, intravenously or
35 orally. Solutions or dispersions of the active compounds
can be prepared in water, suitably mixed with a sur~actant
such as hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols, and

~ 25~
g
1 mixtures thereof, and in oils. Under ordinary conditions
of storage and use, these preparations contain a preserva-
tive to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable
5 use include sterile aqueous solutions or di~persi~ns and
sterile powders for the extemporaneous prep~ration of
sterile injectable solutions or dispersions. For such
uses the form must be sterile and must be fluid to the
extent necessary to provide easy syringability. It must
lO be stable under the conditions of manufacture and storage
and must be preserved against the contaminating action of
microor~anisms such as bacteria and fungi.
The carrier can be a solvent or dispersing
medium containing, for example, water, ethanol, a polyol
15 (for example, glycerol, propylene glycol, and liquid poly-
ethylene glycol, or the like), suita~le mixtures thereof,
and vegetable oils. The proper fluidity can be maln-
tained, for example, by the use o~ a coatlng ~uch as
lecithln, by the malntenance of the required particle size
~ in the case of a dispersion, and by the use of surfac-
tants. Prevention of the action of microorganisms can be
insured by various anti-bacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol, sorbic acid,
thimerosal, or the like. In many cases it may be prefer-
25 able to include isotonic agents, for example sugars or
sodium chloride, in the dosage form. Prolonged absorption
of the injectable formulations can be brought about by
incorporating agents delaying absorption, for examFle,
aluminum monostearate and gelatin, therein.
Sterile injectable solutions are prepared by
incorporating the active compound in the appropriatesolvent, in admixture with various of the other ingredi-
ents enumerated above, as reguired, followed by filtered
sterilization. Generally, dispersions are prepared by
35 incorporating the sterilized active ingredient in a ster-
ile vehicle which contains the dispersing medium and any
other required ingredients. When, on the other hand,
sterile powders are used to prepare sterile injectable

-10--
1 ~olutions, it is preferred to subject a sterile, filtered
solution of the ~esired ingredients to vacuum drying or
freeze-drying, yielding a powder of the active ingredient
plus any additional desired ingredien~s.
As used herein, ~pharmaceutically acceptable,
substantially nontoxic carrier or excipientn includes sol-
~ vents, di~persing media, eoatinys, antibacterial and anti-
fungal agents, isotonic and absorption delaying agents and
the likeO The use of such media and agents as carriers or
excipients for pharmaceutically active substances is well
known in the art. Except insofar as any conventional
medium or agent is incompatible with the active ingredient
or toxic, its use in the therapeutic formulations of the
invention is contemplated. Supplementary active ingredi-
ents can also be incorporated in the therapeuticcompositions.
It may be advantageous to formulate the
compositions of the lnvention ln unlt dosage forms for
ease of administration and uniformity of dosage. A unit
dosage form, as used herein, refers to a physically
discrete unit suitable for use as a unitary dosage for the
mammalian subjects to be treated; each unit contains a
predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association
with the required pharmaceutically acceptable carrier.
Specifications for unit dosage forms are dictated by and
directly depend on (a) the unique characteristics of the
active material and the particular thera~eutic effect to
be achieved, and (b) the limitations inherent in the art
of compounding such an active material for the treatment
of disease in living subjects having a diseased condition,
without excessive cytotoxic side effects.
Regression of leukemia and inhibition of tumor
growth ~ay be attained, for example, by the use of daily
dosing for up to 5 or 10 days, or longer. Multiple
dosing, or dosin~ on any desired periodic basis, may also
be utilized. The therapeutically active ingredient is
thus administered in amounts sufficient to aid regression

~l256~
--11--
l and inhibition of furthcr growth of the leukemia or tumor,
in the absence of excessive deleterious side effects of a
cytotoxic nature.

-12-
1 Brlef Description of the Drawin~
The accompanying drawing is a graph ~howing the
effects of treatment schedule and route of administration
of one of the compounds of the invention in the regression
of L1210 lymphoid leukemia.

-13-
1 Best Mode For Carryln~ Out The Invention
Preferred amony the 5~arboxamido-2-thiobarbituric
acid derivatives hereof are compounds within the scope of
Formula IV above, wherein R and Rl are hydrogen (Example 1
below~, R is 2-chloro and Rl is hydrogen (Example 2)l R is
2-methyl and Rl is hydrogen (Example 3), R i6 3-fluoro and
Rl is hydrogen (Example 4), R is 4-.fluoro and Rl is
hydrogen ~E~ample 5), R is 4-methoxy and Rl is hydrogen
(Example 6), R is 4-ethoxy amd Rl is hydrogen (Example 7),
10 R is 2-fluoro and Rl is hydrogen (Example 8~, R is
2-fluoro and Rl is 4-fluoro ~Example 9), and R is
2-methoxy and Rl is 5-methyl (Example 10). Particularly
preferred is the compound of Example 1, viz., 1,2,3,4-tet-
rahydro-6-hydroxy-4-oxo- N-phenyl-2-thioxo~5-pyrimidine-
carboxamide:
.
The invention will be described in greaterdetail in connection with the following specific examples
illustrating the preparation and pharmacological testing
of preferred embodiments of the compounds of the inven-
tion:
EXAMPLE 1
Preearation of 1,2,3,4-tetrahydro-6-hxd~y
-4-oxo-N-phenyl-2-thioxv-5-Fyrimid~r~c~r~c~ride
A. Reaction of Thiobarbituric Acid with
Phenylisocyanate
14.4 9 of 2-thiobarbituric acid (which may,
alternatively, be named dihydro-2-thioxo-4,6-(lH,5H)-
pyrimidinedione or 4,6-dihydroxy-2-mercaptopyrimi~ine) and
11~9 g of phenylisocyanate were dissolved in dry pyridine

1 (100 ml.). The solution was heated with stirring, and
maintained at 7S-85~C for about 4 hours. Upon cooling,
an orange-colored solid precipi~atled out which was
isolated, washed with about 25 ml dimethylformamide and
dried.
Yield: 16.B g (64~)
NMR (DMSO) 7.1-8.0 d~(multiplet;integral 5); 11.4 ~ (sin-
glet, 1); 12.0-13.7 ~ (broad diffuse peak, 3).
An elemental analysis for CllHgN303S gave the
10 ~ollowing results:
Calculated Found(~)
C 50.19 50.30
H 3.45 4.02
N 15.96 15.75
Mass spectrometric analysis was as follows:
Calculated Found
.. .. _ .
M/E ~ 263 263
The compound decomposed at 310C~. q'he structure was
further confirmed by an X-ray crystallographic study of
2Q the triethylammonium salt.
B. Reaction of Thiourea with _arboxanilidomalonate
Thiourea (1.5g) was intimately mixed with
carboxanilidomalonate, viz., (C2H502C)2 CHCONH ~ ~
(3.6g), and very gently heated in a small flask in an oil
bathO At about 155C the reaction mixture became
semi-liquid with a solid residue remaining in the bo~tom
of the flask. At about l50~C the reaction ~ixture began
to thicken, a volatile material being evolved. The
reaction mixture was heated to 180, left at that tempera-
ture for 1/2 hour, and then cooled. A khaki, ochrecolored powder product was thus produced.
The product was washed with ethanol and dried
(1.89). The mass spectrum was consistent with the prod~ct
of Example lA. Molecular Weight - 263; 171 lpyrimidine
fragment); 93 (anilide fragment).

~ ~ 5 6 8
-15-
1 EXAMPLE 2
Prepafation of N-(2-chlorophenyl)-1,2,3,4-tetrahydro-
6-h,ydroxy-4-oxo-2-thioxo-5-eyrimidinecarboxamide
2-thio~arbituric acid (14.4 9) was carefully
dried, finely powdered and suspencled in dry pyridine (100
ml). The cuspension was warmed with ~tirring to about
- 50, and 2-chlorophenylisocyanate (15.35 g) added. Much
of the suspension went into solution. The mixture was
stirred at 75-85 for 4 hours and left overnight at room
10 temperature.
The pyrimidinecarboxamide was collected as a
purple powder; it was washed with a small quantity of
pyridine, which removed most of the color, resuspended and
triturated in 100% ethanol, collected and dried. Yield
23 g (77%), off-white powder, no sharp melting point
~decomposes above 250C). NMR ~DMS0) 7.1-~.3 ~ ~mul-
tlplet; lntegral 4); 11. ~singlet, 1); 11.7-13.0
~broad dlffuse peak, 3).
Mass Spectrum 299-297 ~molecular ion, chlorine
2~ isotopes); 171 (pyrimidine carbonyl fragment); 129-127
(o-chloroaniline, chlorine isotopes).
EXAMPLE 3
Preparation of 1,2~3 4-tetrahvdro-6-hYdroxY-N
(2-methylphenyl)-4-- ~ -5-pyr mldine-
carboxamide
The procedure described in Example 2 was
repeated, reacting 2-thiobarbituric acid and 2-methyl~
phenylisocyanate to give the pyrimidinecarboxamide as a
tan powder, mp 250 (dec.); NMR (DMSO), 2.30~, singlet,
integral 3; 7.15-B.00 ~ multiplet, 4; 11.4 ~ singlet, 1;
12.0-13.7 ~, broad diffuse peak, 3. Mass Spectrum 277,
171,107.

6~
-16-
1 EXAMPLE 4
aration of N-(3-fluoro~enyl?-lL~L_,4-tetrahydro
-6-hydeoxv-4-oxo-2-thioxo-5-~Yrimidinecarboxamide
The procedure described in Example 2 was
repeated, reacting 3-fluorophenyl isocyanate to give the
pyrimidinecarboxamide as a pinkish powder, mp ~ 250
(dec.) NMR tDMSO); 6.7-7.7 ~ ~ultiplet, integral 4; 11.4
singlet, l; 12-13 3, broad diffuse peak, 3. Mass Spectrum
2~1,171,111.
EXAMPLE 5
Pre~aration of_N-!4-fluoropheny
tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-
pyrimidinecarboxamide
2-thiobarbituric acid (14.4 g) was suspended in
pyridine and 4-fluorophenyl isocyanate ~13.7 g) was added
thereto. The reaction mixture was maintained at 90C for
one hour, and thereafter let overnight a~ room tempera-
ture. The solids formed were collected, washed with
2~ pyridine, re-suspended in ethanol, and again collected and
dried. A pale pink powder product was thereby obtained,
mp ~ 250C (dec.), NMR (DMSO) 7.0-7.7 ~ (multiplet,
integral 4); 10.7-11.4 ~ (overlapping broad singlets,
combined integral 4). MS, M/e 281 (Calc., 2Bl~.
EXAMPLE 6
Preparation of 1L2, 3~4-tetrahydro-6-hydroxy-N-
(4-methoxyphenyl?-4-oxo-2-thiox~-~-pyri~idinecarboxamide
The procedure described in Example 2 was
repeated, reacting 4-methoxyphenylisocyanate to give the
pyrimidinecarboxamide as a yellow powder, mp 330 (dec.),
NMR (DMSO) 3.81 ~ (singlet, integral 3); 6.9-7.6 ~ (two
symmetrical near-doublets, 4); 11.4 ~ (singlet, 1)
11~7-1203 ~ broad diffuse peak, 3. MS, 293,171,1~3.
EXAMPLE 7
Preparation of N-(4-ethoxyphenyl~-1,2,3,4-tetrahydro-
6-hydroxy-4-oxo 2-thioxo~Ryrimidinecarboxamide
The procedure described in Example 2 was

~ s~
-17-
1 repeated, reacting 4-ethoxyphenylisocyanate ~o give the
pyrimidine as a yellowish-pink powder, mp ~ 250 ~dec.),
NMR (~MSO) 1.35 ~ (triplet, integral 3; 4.1 ~ (~uartet,
2) 6.9-7.6 ~ (two symme~rical near-do~blets, 4); 11.4
(singlet, 1) 12-13 ~, low broad diffuse peak. MS
307~171,137.
EXAMPLE 8
Preparation of N-(2-fluorophenYl)-1,2,3,4-tetra-
hydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine-
carboxamide
.
The procedure described in Example 2 wasrepeated, reacting 2 fluorophenyl isocyanate to give the
pyrimidine as a pale pinkish-purple po~der, m.p. ~ 250
tdec.). NMR (DMSO) 7.2-8.4 ~ (complex multiplets), 11.8
(singlet). MS 281, 171, 111.
EXAMPLE 9
Preparatlon of N-~2 4-diEluoro~henYl)-1 2 3 4-
The procedure described in Example 2 wasrepeated, eeacting 2,4-difluorophenyl isocyanate to give
the pyrimidine as a pale pinkish-purple powder, m.p.>
250 (dec.). NMR (DMSO) 7.0-8.3 ~ (complex m~ltiplet),
11.8 ~ (singlet); broad diffuse multiplet ca. 10.7-11.8
MS, 299, 171, 129.
EXAMPLE 10
Preparation of 1,2,3,~ ~e~hv~ ~ xy-
N-(2-methoxY-5-methylphenyl)-4-oxo-2-thioxo-
_ 5-pyri~idinecar~o-xamide
3~
The procedure described in Example 2 was
repeated, reacting 2-methoxy-5-methylphenyl isocyanate to
give the pyrimidine as a pink powder, m.p. ~ 2B0 (decO).
NMR (DMSO), 2.3 ~ (singlet, integral 3); 3.9 ~ (singlet,
35 ~integral 3); 7.0 ~ (broad singlet, integral 2); 7.9
(broad singlet, integral 1); 11.6 ~ (kroad singlet,
integral 1). MS 307, 171, 137.

~ 5 6
-18-
1 Antitumor Activity Of The Compound of Example 1
Tbe spectrum of antitumor activity of the
compound of Example 1 was determin~ed employing a number of
~tandard National Cancer In~titute (NCI) protocols. The
antitumor activity was determined in vivo ~gainst several
different tumors, employing various treatment schedules
and routes of administration. The results ob~ained~
expressed in percent increases in :life-span (% ILS) of the
test animals, are summarized in the following table.

~Lr2~i6
--19--
1 TABLE I
SUMMARY OF ANTITUMOR ACTIVITY OF COMPOUND
OF EXAMPLE 1
Tumor Treatmen~ Activity Rating2
Schedule (% ILS, cures/total)
Murine tumors:
10 i,p. B16 melanoma Days 1~9 +~ (93,85)
s.c. CD8Fl mammary
tumor Staging Day
sOc. Colon 38 tumor Days 2-9
i.p. L1210 leukemia Days 1-9 ~+ (~ 275, 4/6;
~2~, 6/6
s.c. L1210 leukemia Days 1-9 ~ 200, 5/6,
~154,3/6)
i.c. L1210 leukemia Days 1-9 ~ ~34,28)
i.v. Lewis lung
carcinoma Days 1-9
i.p. M5076 sarcoma Days 1-13 ++ (72,2/10;
72)
i.p. P388 leukemia Days 1-5 ~+ (101,94)
Human tumor x~ Lraft:
25 s.r.c. MX-l mammary Days 1-9
tumor
1. The test compound was administered i.p. (intraperi-
toneally) once a day on the days indicated, except in
the case of the test for inhibition of the colon 38
tumor in which it was administered seven times per
day, and the tests for inhibition of the M5076
sarcoma and MX-l mammary tumors ln which it was
administered four times daily.
2. Activity: +~ Reproduced activity: ~ 50~ ILS for i.p. and
i.v. (intravenous)
im~lanted tumors (> 75% ILS for P388),
~90% inhibition of tumor growth for s.c.
~subcutaneous) and s.r,c. (su~renal

~256~6~L
.
-20-
1 capsule), implanted tumors (~ 100~
inhibition for the staged CD8Fl tumor).
+ Reproduced activity: 25-~9~ ~LS for B16,
L1210 and M5076t 20 74% ILS for P388, 40-49
ILS for Lewis lung, 58-89~ 80 8~ and
80-99% inhibition of tumor growth for the
colon 38, xenografts and the staged CD8F
mammary tumor, respectively.
1~
- Inactive.
In both the i.p. and s.c. L1210 leukemia
systems, a 100 mg/kg dose of the test compound
administered i.p. daily for 9 days was curative in at
least 50% of the test mice. The 100 mg/kg dose occa-
sionally demonstrated some toxicity ln the i.p. system.
Employing a 50 mg/kg dose in these systems, Inaximum
lncreased llfe spans of 87-190% were obtained.
Using the same treatment regimen (100 mg./kg.
administered i.p. daily for 9 days), marginal activity
(ILS = 28-34~) was observed against the i.c.
(intracranially) implanted L1210, indicative of a systemic
rather than an i.c. effect.
In the B16 melanoma Cystem~ optimal ILS values
~5 of 93 and 85% were observed following daily i.p. treatment
of 100 mg/kg for 9 days. Activity (ILS = 25%) was
observed over at least a 4~fold dosage range.
In three experiments involving the i.p.
implanted M5076 sarcoma, maximum ILS values of 72, 72 and
48% were achieved after i.p. treatment on days 1, 5, 9 and
13.
- The compound of Example 1 also demonstrated good
activity in the standard NCI lymphocytic leukemia P388
preliminary screen, producing maximum ILS values of 101%,
94% and 62% following i.p. administration of a 50 mg/kg
dose daily during a five day test.
The test compound was ineffective against the
s.c. implanted CD8Fl mammary and colon 38 carcinoma~, the

~L2~r.~68
-21-
1 i.v. implan~ed Lewis lung carcinoma and the s.r.c. human
MX-l mammary carcinoma xenograft under the experimental
conditions employed.
The data obtained in the various tests summa-
rized above are tabulated in Table ][I below. The ratio of
- the survival ~ime for the treated animals tTJ to the sur-
vival time for the control animals ~C~ deter~ined at
Yarying dosages in the respective n vivo tests is set
orth in the table:

~ ~ 5
-22-
1 TABLE II
IN VIVO TEST DATA
FOR THE COMPOUND OF EXAMPLE 1
,, _
NCI TEST DOSE
PROTOCOL ~9~ TREATED/CONTROL PERCENT _
3B131 100 185 193
(i~po~ 50 1~2 1~9
implanted 25 137 158
B 16 12 128
10 melanoma) 6 108
3CDJ2 900 (-) ~-)
(s.c.- 450 (-) (-)
implanted 225 (-) (-)
staged112 85 80
mammary56 85 61
adeno-
carcinoma
CD8Fl)
3C872 900 (_
. .
(s.c.- 450 (-)
implanted 225 51
colon 38112 (~) 68
25 carcinoma) 56 70 120
_
3LE31 DATA SET FORTH IN TABLE III BELOW
(i.p.-
implanted
L1210
leukemia)
3LE32 200 (~) (~)
(s.c.- 100 3~0(5~ 254(3)
imPlanted5~ 140 127
L1210 25 108 99
leukemia) 12.5 109 104

i68~i1
-23-
1 TABLE II (Cont'd)
IN VIVO TEST DATA
FOR THE COMPOUND OF EXAMPLE 1
NCI TEST DOSE
~ROTOCOL mq/kg TREATED/CONTROL PERCENT _
3LE37 200 (-) (-)
(i.c.- 100 128 134
implanted 50 113 108
L1210 25 98 98
g leukemia) 12.5 94 106
3MBG5600 (-)
~s.~.c.300 (-)
human150 (-)
15 mammary75 98
carcinoma
MX-l xeno-
graft)
_
20 3M531 200 (-) (-)
(i.p.- 100 148 172
implanted 50 124 147
M5076 25 101 130
sarcoma) 12.5 117
- - _ _ _ _
3PS31 200 (~
(i.p.- 100 ~-) (-)
implanted 50 162 194 201
P388 25 145 138
30leukemia) 12.5 120
6.25 116
3.13 110
3LL39 100 126
35 (i.v.- 50 115
Lewis 25 106
lung 12.5 103
carcinoma)

S~8~L
24 -
* (~) ~ cures in 'cest at specified dose, (-~=toxic dose,
blank - no test

~2~86~iL
-25-
1 Effects Of Treatment Schedule And Route
Of Administration On The Activity Of The
Compound of ~xample 1 A~jainst s.c.-
__ Implanted L 1210 Leukemia _ _
The influences of ~reatment schedule and routeof administration on the antitumor activity of the
compound of Example 1 were evaluated using the s.c.
implan~ed L1210 leukemia system. The drug was tested in
the form of a freeze dried dosage form containing 50 mg.
of the compound and 100 mg. N-methylglucamine,
reconstituted with 5 ml. of sterile water to yield a 10
mg/ml. solution at about pH 9.5.
The percentage increases in life span ~%ILSI are
shown in the accompanying drawing for different treatment
regimens and routes of administration. As illustrated,
increases in life span were noted using all treatments ~d
routes o~ admlnistratlon save ~or the l.p. and l.v. one
day, one injectlon treatments (tests A and G in the
drawinq). The highest percent ILS was 471 obtained by
daily i.p. injections of the active material on a five day
schedule of 45 mg/kg/injection, corresponding to a total
dose of 225 mg/kg/duration of thR treatment (test C in the
drawing). This dosage also gave 5 cures. Administration
of the drug by oral injection daily for nine days also
resulted in a high percent ILS of 45~, employing a dosage
of 124 mg/kg~injection, and a c~mulative doqe of 1116
mg/kg/duration of treatment (test I in the drawing). Use
of this regimen resulted in 4 cures.
In the studies illustrated in the drawing toxic-
ity was noted with the highest dose in each treatment
schedule except for that involving i.p. administration
every three hours on days one, five and nine of a nine day
test (test F).
It may be seen that, under the experimental con-
ditions utilized, substantial increases in life span ~by
definition, in excess of 25% ILS) were obtained utilizing
each of the routes of administration and treatment sched-
ules save for the single treatment i.p. and ioV~ routes.

6~
-26~
1 Comparison Of The Antitumor Activities Of
Variety Of Test Compounds In The Regression
Of i.p~-Implanted Lymphoicl Leukemia L1210
Samples of the te~t compounds of E~amples 1 - 10
and a number of structurally~related control compounds
were tested in accordance with National Cancer Institute
test protocol 3LE31 (NCI Protocol 1.100, Cancer
Chemotherapy Reports Part 3, Vol. 3, No. 2, September
1972) to determine the effects of the several compounds on
i.p.- implanted L1210 leuke~ia (J. Nat'1. Cancer Inst.
13(5):1328, 1953). Each test involved implantation of the
leukemia cells in six DBA/2 mice, one sex per experiment,
the male mice weighing a minimum of 18 grams and the
female mice weighing a minimum of 17 grams, and all of the
test animals being within a three gram weight range. ~he
test compound was admlnlstered by i.p. injections, ln 0.1
ml. doses o~ dllu~ed ascltlc fluid (105 cells per dose),
commencing one day after the tumor implant and continuing
daily for nine days.
The test animals were weighed and survivors
recorded on a regular basis during a thirty day test
period. The ra~io of survival time for the treated and
control animals (T/C) was determined as a percentage.
The tests were carried out at varying dosage
levels and with varying numbers of repetitions, depending
upon the results obtained with each test compoud. It has
been statistically determined in the 3LE31 test system
that an initial T/C value at least equal to 125% is
necessary to demonstrate activity, while a reproducible
T/C equal to or greater than 125% warrants further study.
A reproducible T/C of 150% or higher i5 considered signif-
icant activity.
The number of mice "cured~, viz., those
surviving from each animal test group after the thirty day
test period, is indicated in parenthesis following the ~/C
percentage data in Table III below:

- 2 7- 3L~
OP~ ff
V ~ r~
.W _~ ~
OP ~ _l _
U C~ _. r~
~ U~
U ~
_ _ ~
U ~ n
N
C U ¦ n u~
E ~ o o 1~ N ~ O L~
4 _ ~ N _1 o
~ ~ N C:~
D X
: . sl:
D
CJ E ¦ ro

-28- ~L2~ i8~i~ .
~ ~ . ~ o ~ .,
~ ~ E~ O ~ ~ ~ ~ _ ~
i' I `D 1`` CO ~0 X 1~ l ~ K t~ J ~ ~
~1 ~ o ~ _ o o r~ _ o o 1~ o ~ _ _
N _ ~ _. _ _ ~ _ _ _ ~ _ _ _ E~
U~ O O O O U~ O O 0 1-~ O O 0 1~- O O O U~
'O O E~ o o o ~ ~1 o o u~l ~ o o IJ'I ~1 o o n
O ~I C _ e~ r~ _ ~ _ ~ -- ~ -~
, ~ _ = = =
'¢' X~ O O O,
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DX U~ U~ U~ u~
~ = = =
a; _ ~
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O I ~ ~ C~, ~
--8Z-- `

-29- l25~
OD ~
U~
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of ,., ,~,
O ~ ~ Q N X X 0~ U~ Q Q u~ Q
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N U~ ~ O O O O U` O O O 1- N . O O O 1~
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Ohl I~ 0 o ~J
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- 31-
D~ ~ ~ N N
E ~ _ _ _ _
D ~ D O~ t` U U~
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_1 ~ ~_-_ _-__ ___ ____ .
_ O O O O U~ O O O U~ O O O L~ O O O U~
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= = ~r
_~ r ~I O ~ _ _
E ~ c ~ 111 lJ ~ r

-32-
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~ ~ _ _ _ _ o ~ ~o ~ o o o o ~ ~ _ o o~ o
o E- _. _ _ _ E~ cr. ~ _ _ _
I,q ~ o o o u~ O o o u~ O O o ~ ~ ~g ~ _ o o o u~
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-33- ~ 8~i1
C ~ r o X ~ I` X X X CO
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36- ~ 1~561~
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~68
o~ U oo o ~o~7~00 ~o~o ~
m o o o u- o o o u O O O U~
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-LE-

~S~8~i~
-38-
1 As may be ~een from Table III, the compound of
Example 1 exhibited significant activity in the
i.p.-implanted lymphoid leukemia test at dosage levels of
both 50 mg/kg. and 100 mg/kg., and produced a number of
cures at 100 mg/kg. With the exceFtion of the compound of
Example 5, the materials of the oth~er examples similarly
exhibited significant activity in the test. On the other
hand, only two control compounds, the barbituric acid
derivatives of Controls B and Ct exhibited significant
10 activity in the test. The compound of Control Ay
previously believed to exhibit moderate activity in the
3LE31 test protocol, was found upon further testing to
exhibit a T/C less than 125~ and thus to be inactive.
From the preceding, it will be seen that, in
15 accordance wlth the present lnvention, a class of novel
5 pyrimidlnecarboxamldes ls provided, the members of whlch
exhlblt substantlal cytotoxlc activity and induce regres--
sion and/or inhibit growth of leukemia and various malig-
nant tumors in mammals. It will be apparent that various
changes may be made in the method of preparation and use,
as well as in the particular substitution, of the thera-
peutically active compounds of the invention. Accord-
ingly, the preceding disclosure should be construed as
illustrative only, and the scope of the invention should
be inter~reted in accorclance with the claims appended
hereto.
3~