CA1256860A - 5- pyrimidinecarboxamides and thiocarboxamides and treatment of leukemia and tumors therewith - Google Patents

Abstract

Case 5993 KON 2A
ABSTRACT
Novel 5-pyrimidinecarboxamides and thiocarbox-amides useful for regressing or inhibiting the growth of leukemia and tumors. The compounds have the formula:

wherein R1 and R2 are each independently hydrogen;
alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms, or a carbohydrate residue;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms;
nitro; cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W is oxygen or sulfur;
X is sulfur or selenium; and Y and Z are each independently oxygen, sulfur or selenium; and the pharmacologically acceptable addition salts thereof.

Description

~ 8~ case 5993 KON 2A

~t~
1 5-PYRIMIDINECARBOXAMID~5 ~ND THIOCARBOXAMIDES
AND TR~ATMENT OF LEUKEMIA AND TVMORS THEREWITH
Technical Field This invention relates to new 5-pyrimidine-carboxamides and thiocarboxamides, and the pharmacologi-cally acceptable addition salts and nucle~sides thereof.
More particularly, the invention relates to new 5-pyri-midinecarboxamide and thiocarboxamide derivatives which have anti-leukemia and anti-tumor activity, to phar-10 maceutical compositions containing such derivatives as thetherapeutically effective constituents thereof, and to a method utilizing the same for inducing the regression of leukemia and/or the inhibition of growth of tumors.

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3L25~86 1 Background Art 5-pyrimidinecarboxamides, and particularly 5-carboxamides of barbituric acid, have previously been described as potential anti-cancer agents. Thus, Takeda S Pharmaceutical Industries' Japanese Patent Publica~ion No. 1,445/64, published on February 14, 1964, suggest~ the use of compounds of the formula:

;~d-~

~ 11 t3 l.e., S-phenylcarbamoylbarhlturic acid (wherein R is hydrogen) and l-substituted-phenylcarbamoylbarbituric acids (wherein R ls alkyl or phenyl), for such purpose.
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. ~ull.
(Tokyo) 8, 1021-1028 (1960).
Analoys of similar barbituric acid derivatives have also been described in the literature. Thus, N-sub-stituted~2-amidocarbonylthiobarbituric acids of the formula:
o ~ X
R2 ~ ~e - NH - Rl l3 wherein Rl is alkyl, alkenyl, various substituted alkyl, 8~) --4~
1 alkenyl or carbonyl, or optionally substituted aryl or aralkyl, R2 and R3 each independently is alkyl, alkenyl, cycloalkyl, aryl, aralkyl or hydrogen, provided that not more than one of R2 and R3 is hydrogen, and X is oxygen or sulfur, are disclosed in Bayer AG German Offen. 24 05 732 and in Rramer et al., U.S. Patent No. 3,961,061 granted on June 1, 1976. These thiobarbituric acid derivatives are described as possessing insecticidal, acaricidal, fungicidai and bactericidal properties.
Other 5-carboxamido-substituted thiobarbituric acids such as:

~ 01~
~ R5 I

~2 wherein X is oxygen or sulfur, Rl and R2 may each be alkyl, alkenyl, benzyl or unsubstituted or substituted phenyl, R3 may be halogen, nitro or trihalomethyl, R4 is hydrogen, halcgen or trihalomethyl, and R5 is hydrogen, halogen, methyl or methoxy, are also described in the patent literature. Such co~pounds are disclosed in Ciba-Geigy European Patent Publication No. 74,335 and in De Sousa et al., U.S. Patent No. 4,283,444 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 inventionto provide a new class of 5-pyrimidinecarboxamides and thiocarboxamides, in particular a new group of 5-carbox-amido or 5-thiocarboxamido-2-thio or 2-selenobarbituric 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 inven~ion will be apparent from the ~2~

1 following detailed descriptlon of preferred embodiments thereof .

-6- ~ 2 ~ ~ ~6 1 SummarY of the Invention Compounds useful in the practice of the present invention are the 5-carboxamido or 5-t:hiocarboxamido derivatives of 2-thio- or 2-selenobarbituric acid~ of the S formula:

Y
¦ I R3 . ~ C N<

~IV) l l X~ ~ ~Z~

~1 wherein Rl and ~2 may each independently be hydrogen;
alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one 25 to six carbon atoms; or a carbohydrate residue;
R3 is hydrogen, Cl-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, na~hthyl, benzyl, naphthylmethyl, thienyl, ~hienyl~ethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms;
nitro, cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
35 naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W is oxygen or sulfur;
X is sulfur or selenium; and -7~
1 X is sulfur or selenium; and Y and Z may each independently be oxygen, sulfur or selenium; and the pharmacologically acceptable addition salts ~hereof.
When Rl and/or R2 is hydrogen, addition salts may be formed with a variety of pharmacologlcally accepta-~ ble organic and inorganic salt-forming reagents. Useful addition salts may thus be formed by admixture of the organic acid with one equiYalent of a base, e.g.~ an organic a~ine such as triethylamine or N-methyl glucamine, and inorganic cations such as sodium, potassium or the like. The addition salts of the organic acids of the invention are, in general, crystalline solids which are relatively insoluble in both polar solvents such as water, methanol and ethanol, and non-polar organic solvents such as dlethyl ether, benzene, toluene and the like. They are ~omewhat soluble in ap~otic solvents such as dlmethyl~o~mamide and dlmethylsulPoxide.
On the other hand, when Rl or R2 is a carbohy-Z drate residue it may be furanosyl (e.g.~ arabinofuranosylor ribofuranosyl), pyranosyl (e.g., arabinopyranosyl, glucopyranosyl, rhamnopyranosyl, or xylopyranosyl~, their deoxy derivatives, or their aliphatic analogs (e.g., hydroxyalkoxyalkyl or polyhydroxyalkyl groups havins from ~ 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 residue" is intended to refer to those cyclic and acyclic groups which form pyrimidine nucleosides or pseudo nucleosides, e.g., materials including both the cyclic and acyclic groups specified hereinabove.
The S-car~oxamido or thiocarboxamido

2-thio-barbituric acid derivatives can exlst in the form illus~rated in Formula IV or in any of its tautomeric forms. For ease of understanding, the compounds of the invention will only be illustrated herein in the form shown in Formula IV but will be understood to embrace the tautomers thereof, or tautomeric mixtures.

6~36~) 1 Amongst the preceding zompounds, those 5-pyrimidinecarboxamides and thiocarboxamides wherein ~1 and R2 are each hydrogen, or wherein one of Rl or R2 is hydro~en and the other is a carbohydrate residue, are novel. In addition, the 5-pyrimidinecarboxamides and thiocarboxamides of 2-selenobar-bituric acid are also - novel compounds.
The 5-carboxamide-2-thiobarbituric acid derivatives may be readily prepared by reacting 2-10 thiobarbituric acid with phenyl isocyanate or an appropri-ate substituted phenyl isocyanate, in the presence of a solvent or dispersing medium such as dimethyl sulfoxide, pyridine, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, sulfolane, tetrahydrothiophene oxide, acetonitrile, or a tertiary amine such as triethylamine.
The molar proportlons of the 2-thiobarblturic acid to the phenyl isocyanate reactant may range from a~out 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 160~C; in most cases, the reaction proceeds quite well at tempera-tures 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 about 2 to 4, hours.
Alternatively, the carboxamides and thiocarboxamides hereof may be prepared by other routes.
For example, thiourea may be reacted with appropriately s~bstituted 2-aroylamino propanedioic acid diesters (pre-pared in known manner by reacting malonic acid diesters with appropriate substituted or unsubstituted aryl isocyanates), and the resulting products separated and recovered. If desired, an appropriate S-substituted psuedo thiourea NH
R - S - C ~

1 may be employed in the reaction instead of thiourea, and the resulting 2-substituted thiopyrimidinyl compound reacted with hydrogen ~ulfide or an alkali metal or ammonium salt thereof (e.g., NaSH) to form the ~esired 2-thioxo pyrimidinecarboxamide or thiocarboxamide.
The compounds of the invention may also be pre-pared by reacting the corresponding unsubstituted pyrimidines with a dialkyl sulfate or other alkylating agent, reacting the 2-(alkylthio) pyrimidinedione thus formed with an appropriate unsubstituted or substituted aryl isocyanate to form the desired 5-carboxamido or thiocarboxamido moiety, and reacting that product with hydrogen sulfide or an alkali metal or ammonium salt thereof to form the desired product.
It may also be possible to prepare the carboxamide or thiocarboxamide compounds by simply displacing the amlno groups on the correspondlng 2-amino-pyrl~idlnecarboxamides or thiocarboxamides, or the alkali metal or ammonium salts thereof thereby forming the desired compounds of the present invention.
The carboxamides and thiocarboxamides of 2-selenobarbituric acid are pre~ared by reacting selenourea with the appropriate 2-aroylamino propanedioic acid diesters in the manner described above.
The compounds of the invention are cytotoxic agents useful to induce the regression of blood malig-nancies such as leukemia, as well as to inhibit ~he growth 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 "regres-sion~ and ~inhibition" comprehend arresting or retarding the growth of the malignancy or other manifestation of the disease, as compared with the course of the disease in the absence of treatment.
Administration of vario~s of the 5-pyrimidine carboxamides and thiocarboxamides of the invention to mice in amounts ranging from about 12-200 mg./kg., preferably from about 25-100 mg~/kg., of body weight has been found ~256~60 1 effective to induce the regression of leukemia and to inhibit the growth of tumors. The interrelationship of dosages for mammals of other sizes and species is described by Freireich, E.J., et al., Quantitative Com-S parison of Toxicity of Anti-cancer Agents in Mouse, Rat, ~amster, Dog. Monkey and Man, Cancer Chemotherapy, Reg.
- S0, No. 4,219-244, May 1966.
The dosage level may, of course, be adjusted to provide optimum therapeutic response. For example, sev-10 eral divided doses may be administered daily, or the dosemay be proportionally reduced, as indicated by the exigencies of the therapeutic situation.
The active compounds may suitably be administered parenterally, intraperitoneally, intravenously or orally. Solutions or disper~ions of the active compounds can be prepared in water, suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersions can also be prepared in glyce~ol, liquid poly-ethylene glycols, and mixtures thereof, and ~n oils.
Under ordinary conditions of storage and u~e, these prepa-rations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemForaneous pre~aration of sterile injectable solutions or disFersions. For such uses the form must be sterile and must be fluid to the extent necessary to provide easy syringability. It must be stable under the conditions of manufacture and storage and must be preserved against the conta~inating action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersing medium containing, for example, water, ethanol, a polyol (for exa~ple, glycerol, propylene glycol, and liquid poly-ethylene glycol, or the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be main-tained, Eor example, by the use of a coatin~ such as lecithin, by the maintenance of the required particle si2e ~2~68~) 1 in the case of a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be insured by various anti-bacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, vr the like. In many cases it may be preferable to include isotonis agents, for example - sugars or sodium chloride, in the dosage form. Prolonged absorption of the injectable formulations can be brought abou~ by incorporating agents delaying absorption, for 10 example, aluminum monos~earate and gelatin, therein.
Sterile injectable solutions are prepared by incorporating the active compound in the appropriate solvent, in admixture with various of the other ingredi-ents enumerated above, as required, followed by fi:Ltered 15 sterilization. Generally, dispersions are prepared by incorporating the sterillzed actlve ingredient in a ster-lle vehicle which contains the disperslng medlum and any other requlred lngredlents. When, on the other hand, sterile powders are used to prepare sterile injectable 20 solutions, lt is preferred to subject a sterile, filtered solution of the desired ingredients to vacuum drying or freeze-drying, yielding a powder of the active ingredient plus any additional desired ingredients.
As used herein, Hpharmaceutically acce~table, 25 substantially nontoxic carrier or excipient" includes sol-vents, dispersing media, coatings, antibacterial and anti-fungal agents, isotonlc and absorption delaying agents and the like. 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 i5 conte~plated. Supplementary active ingredi-ents can also be incorporated in the therapeutic compositions.
It may be advantageous to formulate the compositions of the invention in unit dosage forms for ease of administration and uniformity of dosage. A unit ~:5~36~

1 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 ef~ect, in association with the required pharmaceutically ,acceptable carrier.
- Specifications for unit dosage forms are dictated by and directly depend on (a) the unique characteris~ics of the ac~iYe material and the particular therapeutic effect to 10 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 15 gro~th may be attained, for example, by the use of daily dosing for up to 5 or 10 days, or longer. Multiple dosing, or dosing on any desired periodlc basis, may also be utillzed. 'rhe therapeutically actlve ingr~dlent is thus administered ln amounts sufficient to ald regression 20 an~ inhibition of further growth of ~he leukemia or tumor, in the absence of excessive deleterious side effects of a cytotoxic nature.

86~

1 Best_Mode For Carry~ Out The Invention Preferred among the 5-pyrimidinecarboxamides and thioc~rboxamides of the invention are those compounds within the scope of Formula IV above, wherein:
Rl and R2 are hydrogen atoms or carbohydra~e residues;
R3 is hydrogen;
R4 is phenyl, 2- or 3-halophlenyl, 2-me~hyl-phenyl, 2,4-difluorophenyl, 4-fluorophenyl, 10 2-methoxy-5-methylphenyl, 4-(Cl-C6) alkoxyFhenyl, 2-- or 4-trifluoromethylphenyl, or hydroxyphenyl;
X is sulfur; and Y, W and Z are oxygen.
This subgeneric class of compounds is disclosed and 15 claimed in copending Canadian Applicatlon Serial No. 470,497, filed December 1~, 1984, entitled "5-PYRIMIDINECARBOXAMIDES AND TREATMENT OF LEUKEMIA AND

TUMORS THEREWIT~".
Particularly preferred members of the subgenus 20 are those wherein R3 is hydrogen and R4 is phenyl (~xample 1 below), 2-chlorophenyl (Example 2), 2-methylphenyl (Example 3), 3-fluorophenyl (Example 4), 4-fluorophenyl (Example 5), 4-methoxyphenyl (Example 6), 4-ethoxyphenyl (Example 7), 2-fluorophenyl (Example 8), 2,4-difluoro 25 phenyl (Example 9), or 2-methoxy-5-methyl~henyl (Exa~ple 10), To date, best results have been obtained with the compound of Example 1, vi~., 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidine-carboxamide.
The invention will be described in greater detail in connection with ~he following specific examples illustrating ~he preparation and pharmacological testing of preferred embodiments of the compounds of the inven-tion. In the examples all temperatures are given in 35 degrees Celsius and proportions in parts ~y weight.
I. PREPARATION OF COMPOUNDS OF THE INVENTION

,, t;~

~L2~

1 Preparation of 1~2~ 5~3lD~u ~-hydro~x~
-4-oxo-N-phenyl-2-thio_o-5 ~y~imidinecarboxamide A. eaction of Thiobarbituric Acid With Phenyl Isocvanate 14.4 g of 2-thiobarbituric acid (which may, alternatively, be named dihydro 2-thioxo-4,6-(lH,5~)-pyrimidinedione or 4,6-dihydroxy-2-mercap~opyrimidine) and 11.9 9 of phenyl isocyanate were di~solved in dry pyridine (100 ml.). The solution was heated with stirring, and 10 maintained~at 75~-85C for about 4 hours. Upon coolin~, an orange-colored solid precipitated out which was isolated, washed with about 25 ml dimethylformamide and dried.
Yield: 16.8 g (64%) NMR ~DMSO) 7.1-8.0 S (multiplet;integral 5); 11.4 ~ (sin-glet, 1); 12.0-13.7 ~ (broad diffuse peak, 3),.
An elemental analysis for CllHgN3O3S gave the ~ollowing results:
Calculated Found(%) ~0 C 5~.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~. The ~tructure was further confir~,ed by an X-ray crystallo~
graphic study of the triethylammonium salt.
B. Reaction of Thiourea with Carboxanilidomalonate Thiourea (1.5g) was inti~ately mixed with carboxanilidomalonate, viz., (C2H502c)2 CHCONH ~
(3.6g), and very gently heated in a small flask in an oil bath. ~t about 115C the reaction mixture became semi-liguid with a solid residue remaining in the bottom of the flask. At about 150C the reaction mixture began to thicken, a volatile material evolving. The reaction mixture was heated to 180, left at that temperature for 1/2 hour, and then cooled. A khaki, ochre colored powder product was thus produced.

5~36(:~

1 The product was washed with ethanol and dried (1.8g). The mass spectrum was consistent with the product of Example lAo Molecular Weight - 263; 171 (pyrimidine fragment); 93 (anilide fragment).
æXAMPLE 2 Preparation of ~ enyl)-lJ2,3~4-tetrah~dro-~hX ~ xo-2-thloxo-5-pyrimidinecarboxamide 2-thiobarbituric acid (]4.4 g) was carefully dried, finely powdered and suspended in dry pyridine (100 10 ml). The suspension was warmed (with stirring) to about 50, and 2-chlorophenyl isocyanate tl5.35 g) added. Much - of the suspension went into solution. The mixture was stirred at 75-85 for 4 hours and lef~ overnight at room temperature.
The pyrimldinecarboxamide was collected as a purple powder; it was washed with a small quantity of pyrldlne, whlch removed most of the color, re-suspended and triturated ln 100% ethanol, collected and dried.
Yield 23 g (77%), off-white powder, no sharp ~elting point 20 (decomposes above 250C). NMR (DMSO) 7.1-8.3 ~ (mul-tiplet; integral 4); 11.8 ~ (singlet, 1); 11. 7-13.0 (broad diffuse peak, 3).
Mass Spectrum 299-297 (molecular ion, chlorine isotopes); 171 (pyrimidine carbonyl fragment); 129-127 (o-chloroaniline, chlorine isotopes).

PreParation of 1 2,3 4-tetrahYdro-6-h~droxY-N-o-2-thl~ ~ e-carboxamide ir~e~ procedure described in Example 2 was repeated, reacting 2-thiobar~ituric acid and 2-methyl-phenyl isocyanate to give the pyrimidinecarboxamide as a tan powder, mp 250 (dec.); NMR (DMSO), 2.3 ~ , singlet, integral 3; 7.15-8.00 ~ multiplet, 4; 11.4 ~ singlet~ 1;
12.0-13.7 ~ , broad diffuse peak, 3. Mass Spectrum 277, 171,107.
EXAMPLE ~
Preparation of N-(3-flu~ yl) ~l~ ~ ro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide ~ ~ 5 ~ ~6 1 The procedure described in Example 2 was repeated, reacting 3-fluorophenyl isocyanate to give the pyrimidinecarboxamide as a pinkish powder, mp ~ 250 (dec.) NMR (DMSO); 6.7-7.7 ~ multiplet, integral 4; 11.4 singlet, 1; 12-13 ~ , broad difuse peak, 3. Mass Spec-trum 281,171,111.
-~ ~ ~J~

Preparation of N-(4-fluoroPhenyl)-1!2,3,4-t ~ 6-hydroxy-4-oxo-2-thioxo-5 ~yrlmidinecarboxamide ~ ~.
2-thiobarbituric acid (14.4 g~ was suspended in pyridine and 4-fluorophenyl isocyanate (13.7 9) was added thereto. The reaction mixture was maintained at 90C for one hour, and thereafter left overnight at room tempera-ture. The solids formed were collected, washed with 10 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 single~s, combined inteyral 4). MS, M/e 281 ~Calc., 281).

Pre~aration of 1,2~3~4-tetrahydro ~ ro~
(4-meth~yphenyl)-4-oxo-2-thloxo- ~ lldlnecarboxamide The procedure described in Example 2 was repeated, reacting 4-methoxyphenyl isocyanate to give the pyrimidinecarboxamide as a yellow powder, m.p. ~ 330 (dec.), NMR (DMSO) 3.81 ~ (singlet, integral 3); 6.9-7.6 (two symmetrical near-doublets, 4~, 11.4 ~ (singlet, 1);
11.7-12.3 ~ , broad diffuse peak, 3. MS, 293,171,123.

Preparation of N (4-ethoxyphen 1)-1,2,3,4-tetrah dro-6-hydroxy~4-oxo-~-thioxo-5~yrYmidinecarboxamide The procedure described in Example 2 was repeated, reacting 4-ethoxyphenyl isocyanate to give the pyrimidine as a yellowish-pink powder, mp ~ 250 (dec.), N~R (DMSO) 1.35 ~ (triplet, integral 3; 4.1 ~ (quartet, 2); 6.9-7.6 ~ ~two symmetrical near-doublets, 4); 11.4 S
(singlet, 1); 12-13 ~ , low broad diffuse peak. MS
307,171,137.

Preparation of N-2(2-fllorgeh~y~ 2~ etra-hydro-6-hydro~ -4-oxo-2-thioxo-5-Pyrimidine-carboxamide ~.25~

1 The procedure described in Example 2 was repeated, reacting 2-fluorophenyl isocyanate to give the pyrimidine as a pale pinkish-purple powder, m.p.) 250 (dec.)O NMR (DMSO) 7.2-8.4 ~ (complex multiplets), 11.8 (singlet). M5 281, 171, 111.

~ Preparation of N-(2,4-difluorophenyl ? ~ 4_ -4-oxo-1-thioxo-5-~ rlmldlnecarboxamide The procedure described in Example 2 was repeated, reacting 2,4-difluorophenyl isocyanate to give the pyrimidine as a pale pinkish-purple powder, m.p.~
250 tdec.). NMR (DMSO) 7.0-8.3 ~ (complex multiplet), 11.8 ~ (singlet); broad diffuse multiplet ca. 10.7-11.8 MS, 299, 171, 129.

Preparatlon of 1~2~3~4-t~y~
N-~2-methox~-S-methYl~henyl)-4-oxo-~~th oxo _ ^ 5-pyrlmidin~ecarboxamide The procedure described in Example 2 was repeated, reacting 2-methoxy-5-methylphenyl isocyanate to give the pyrimidine as a pink powder, m.p. > 280 (dec.).
NMR (DMSO), 2.3 ~ (singlet, integral 3); 3.9 ~ (singlet, integral 3); 7.0 ~ (broad singlet, integral 2); 7.3 (broad singlet, integral 1); 11.6 ~ (broad singlet, integral 1~. MS 307, 171, 137.

Preparation of 1,2,3,4-tetrahydro-6-hydroxy-1,3-dime'thyl-4-oxo-N-~henyl-2-thioxo-5-pvrimldi-necarboxamide A. Reaction of N,N-dimethyl th obarbituric acid and pher.yl isoc~anate, with triethylamine N,N'-dimethyl-2-thiobarbituric acid (109) was suspended in toluene (250 ml), and triethylamine (7.19) followed by phenyl isocyanate (8.269), was added thereto.
The solids went into solution. The reaction mixture was heated under reflux for 12 hours, and the solvent was thereafter removed in vacuo. The residue was triturated ~ ;~5~

l with dilute HCl, filtered and recrystalli~ed fro~ glacial acetic acid, to yield the pyrimidinecarboxamide as pinkish-buff needles, m.p. 194-196, 13.6g. N~R (CICl3)

3.78 S (singlet, in~egral 6), 7 25-7.55 ~ (multiplet), integral 4), 11.8 ~ and 18.3 S , broad singlets.
B. Reaction without tr ~
_ - The reaction was carried out as in Part A,using lOg of N,N'-dimethyl-2-thiobarbituric acid, and 8.269 of phenyl isocyanate in pyridine, without triethylamine. The reaction mixture was gently warmed for 2 hours, cooled and acidified with dilute ~Cl. A pinkish solid resulted, which was collected, washed with water, suspended in ethanol, warmed, and filtered hot. The filter-cake was recrystallized from glacial acetic acid to yield a buff - 15 colored solid, essentially identical to that obtained in Part A, m.p. 193.

PreDaration of 1 2 3 4-tetrahYdro-6-hYdroxY-4-oxo-N-1~3-triphenyl ~-th~oxo-1,3-diphenyl-2-thiobarbituric acid (lOg) was dissolved in the minimum quantity of dimethyl sulfoxide (DMSO), and triethylamine (3.5g) was added thereto~
Phenyl isocyanate (4.5g) was added to the solution with stirring, the mixture was gently warmed for 2 hours, and then po~red into water. The solid so produced was separated, dried and recrystallized from glacial acetic acid to give fine off-white needles, m.p. 291.5-293.
NM~(DMSO); 7.2-7.5 ~ (multiplet); and several other peaks too diffuse to assign accurately.
~XAMPLE l3 Preparation of 1,2,3,4-tetrahYdro-6-hydroxy-3-methvl-

4-oxo-N-phenyl-2-thioxo-5-pyrimidinecarboxamlde N-methyl-2-thiobarbituric acid (lOg) was dis-solved in DMSO, and triethylamine (9.79), followed by phenyl isocyanate (8.26g), was added. The mixture was warmed for several hours. On cooling, a crop of white needles appeared. These were collected, suspended in hot HCl, collected, and dri~d, giving an off-white powder m.p.

~ 86 1 252-254. NMR(DMSO; 3.53 ~ (singlet integral 3); 7.2-7.6 ~ , (multiplet, integral 4): 11.4 ~ , broad singlet, integral l; broad diffuse absorption about 5.2-6.7 ~ .

PreRaration of 2~[[(1,2~3,4-tetrahydro-6-h droxy-4-oxo-1,3~dlphen~1-2-thioxo-5-p~ C~r~
car_onyl]amino]-benzoic acld met:hyl ester N,N'-diphenyl-2-thiobarbituric acid (89) was dissolved in the minimum quantity of DMSO, and 10 triethylamine (4g~ was added, followed by a solution of 2-carbomethoxyphenyl isocyanate (5.19) in a little DMSO. The mixture was warmed and left overnight. A crop of yellowish-buff crystals was collected, and triturated with dilute HC1. The product was collected, washed with water 15 and dried, giving a buff-yellow powder with no sharp melting-point. Decompositlon beglns at about 230.
NMR(DMSOJ; 3.8 ~ (singlet integral 3); 7.2-8.3 d (complex multiplet, integra} 14); 12.5 d^ ~broad singlet, integral 1).

Preparation of N-(4-chlorophen~_-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pS~rimidlnecarboxamide The preparation was carried out as described in Example 14, reacting N-phenyl-2-thiobarbituric acid and 4-Z5 chlorophenyl isocyanate to give a pinkish powder product - which did not have a sharp melting-point, and which decomposed between 170 and 185. N~R(DMSO); diffuse broad peak, 4.7-5.6 ~ ; 7.2-7.7 ~ (multiplet~; 8.8 (broad singlet).

PreEaration f N-(3,4-dichlorophenYl~-1,2,3,4-tetrahydro-6-h~droxy-4-oxo-2-thiox_-5-pyr _idinecarboxamide 2-thiobarbituric acid (7.2g) was suspended in dry DMF, and triethylamine (6.9g~ was added. To this was added a solution of 3,4-dichlorophenyl isocyanate in DMF, ~nd the reaction mixture was warmed gently for several hours, cooled and poured into dilute hydrochloric acid~ a copious pinkish-white solid orming. The product wa~

1 collected, re suspended in ethanol, collected again and dried, giving a pinkish solid, m.p. ~ 275 (dec)~
NMR(DMSO); 7.5-7.75 ~ ,two broadened peaks typical of 4-chlorophenyl compounds; other peaks too diffuse to 5pecify.
EXAMPL~ 17 - Pre~aration of N-(4-hut ~ hen~ 1,2,3,4-tetr~hyd~o-6-ydroxy-3-methyl-4-oxo- -thioxo-5-~yrimidinecarboxamide The preparation was carried out as described in 10 Example 11, reacting 7.7g of ~-methyl-2-thiobarbituric acid with 8.8g. of 4-butylphenyl isocyanate to give a pale pinkish solid, m.p. 190 (dec); NMR(DMSO~; 0.6-1.7 ~, ~overlapping triplet and multiplet, integral 7~; 2.5 ~ , peak obscured by coincidental DMSO D5 signal 3.5 ~ , 15 (singlet, integral 3); 6.9-7.5 ~ (multiplet, integral 4);
8.7 ~ and 11.4 ~ , di~fuse peaks.

Preparation of 1,2,3,4-tetrahydro-6-hydroxy-3-meth 1-4-oxo-N-phenyl~2~-hio~~5=~rlmidinecarboth~ _ N-me~hyl-2-thiobarbituric acid (9.5g) W2$ dis-solved in the minimum quantity of ~MSO, and triethylamine (8.4g) was added thereto, followed by phenyl isothiocyanate (8.2g) in a little DMSO. The mixture was warmed for several hours, cooled and poured into dilute 25 hydrochloric acid. A copious pink solid appeared; the æolid was collected, washed with water and ethanol and driedl giving an amorphous gray powder product. The product melted with decomposition at ca. 245. NMR(DMSO);
3.6 ~ (singlet, integral 3); 6.96 ~ (singlet, integral 1);
~0 7.2-7.6 ~ , multiplet, integral 5; 13.6 ~ , broad sin-glet, integral 1. M.S. M/e 293, calc. 293.

Pr~ ion of 1,2,3,4-tetrahydro-6-h droxy-N-(l-na ~ 4-oxo-2-thiox -5 ~ rboxa~ide 2-thiobarbit~ric acid (lOg) was suspended in pyridine and l-naphthalenyl isocyanate (ll.lg~ added. The reaction mixture was maintained at 90 for 1 hour, and then left overnight at room temperature. The solids were ~L~5~

1 collected, washed with a little pyridine, then suspended in ethanol, and collected again and dried, giving a pinkish-yellow powder product, m.p.305~310 (decomp).
NMR(DM50) 7.3-8.3 ~ (multiplet, integral 7); 11-13 ~
(overlapping diffuse peak and broad singlet, integral 4).

Preparation of 112, 3 ~ 4-tetra~ ~
-thioxo-N-(3,4,5-trlmethoxyphe~ 5-pyrimidinecarboxamic The preparation was carried out as described in 1~ Example 19, using 2-thiobarbituric acid and 3,4,5-trimethoxyphenyl isocyanate to give a pinkish powder product, m.p. ~ 310(dec)~ NMR(DMSO) 3.66 ~ (singlet, integral 3); 3.80 ~ (singlet, integral 6); 6.95 ~ (sin-glet, integral 2): 11.9 ~ (singlet, integral 1); 12-13 (broad diffuse peak).
EX~MPLE 21 Preparation of lL~ 4-tetrahydro-6-h~
~2-methyl-5-nltrophenyl~-4-oxo 2-thioxo-5-p,~rlmidlnecarboxamide The preparation was carried out as described in Example 19, using 2-methyl-5-nitrophenyl isocyanate to give a pale yellow powder, m.p. ~ 300(dec), NMR(DMSO) 2.35 ~ (singlet, integral 3); 7.35-7.85 ~ (multiplet, integral 4); 11.4 ~ (singlet, integral 1); 12-13.5 ~(broad diffuse peak).

Preparation of 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-p enyl- -(2-~ropenyl)-2-thloxo-5 pyrlmldlnecar~oxamlde N-allyl-2-thiobarbituric acid (20g) was dis-solved in pyridine (300 ml) and triethylamine (15.2ml) and phenyl isocyanate (13g) were added thereto. The reaction mixture was stirred at 80-90 for 4 hours, cooled, solids collected, treated with dilute HCl, washed with water and ethanol, and dried. The product was an off-white solid, 3~ m.p. 209-211. N~R(DMSO) 4.8-6.2 ~ (complex multiplet, integral 5); 7.2-7.7 ~ (multiplet, integral 5): 11.4 (singlet, integral 1) broad diffuse peak at 10 ~ 8~iO

1 Preparation of 1,2,3,q tetrahydro 6-hydroxy-4-oxo~N-phen~1-2-selenoxo-5-~r imidinecarboxamide Selenourea t4g) and 2-(benzoylamino) pro-panedioic acid diethyl es~er (9g) were intimately mixed under a nitrogen atmosphere and gent:ly heated in an oil-bath. At a bath temperature of about 120 the reac~ion mixture liquified. At about 140 a clear liquid began to distill out; as the distillation proceeded the reaction mixture began to solidify. The bath was maintained at 10 145 for a few minutes longer; the reaction mixture was then cooled, triturated with hot ethanol and filtered hotO
The filter-cake was re-suspended in hot ethanol, triethylamine added until most solids had gone into solution, ~iltered from the insolubles and cooled. The pyrimidine derivative, as a triethylamine salt, crys-tallized out as an ochre solid, m.p. 190 ~decomp). NMR
1.1-1.3 ~ (triplet, integral 9); 2.9-3.3 ~ (quartet, integral 6); 6.8-7.7~multiplet, integral 5); 11.8 ~
(broad singlet, integral l); broad diffuse absorption about 10-11 ~ . Mass spectrum, M/e 307,308,309,311,313 (calculated, 307,308,309,311,313; selenium isotopes with observed abundance ratios very close to natural ratios.
II . PHARMACOLOGICAL TESTING OF COMPOUN~S OF THE I~VENTION
As described in the aforesaid, concurrently filed application Serial No. 470,497 [247-19 CIP(IA)], the compounds of Examples 1-10 have been found to exhibit anti-leukemia and anti tumor activities in certain in vivo tests. Other compounds within the scope of Formula IV have not exhibited acti~ity in in vivo testing to date (see, for example, Controls A and H-X in Table III
of the aforesaid application). However, those compounds within the scope of the present invention which have heretofore been tested have been found to exhibit in vitro activity against L-1210 leukemia cells, i.e., they are cytotoxic to such leukemia cells. These compounds may thus exhibit anti-leukemia or anti-tumor activities when subjected to o~her in v o test protocols.

;`h~

-24~
1 The cytotoxicit~ of various representative compounds within the class of materials of Formula IV wa5 tested, in vitro, against L-1210 leukemia cells (J. Nat'l.
Cancer Inst. 13(5~:1.328, 1953), as follow~:
L 1210 cells growing in a log phase tlx105 cells per ml, 5 ml per flask) were incubated for 24 hours with the test compounds (0.1 m molar solutions of the various compounds were prepared in DMSO and the appropriate amounts added to 5.0 ml of the cell culture medium to 10 provide final concentrations of between 1.0 m molar and 1.0 u molar) in RPMI 1630 medium and 2 m molar L~glutamine containing 18# fetal calf serum. The cells were then counted in a Coulter counter. Inhibitory concentration -50 (ICso) values were extrapolated from the L-1210 cell 15 growth in admixture with var.ious concentrations of the test compounds, as compared with the growth of the control cells~ Under the conditions of the assay, the control cells exhiblted a doubling tlme of 11 to 13 hours. The ICso values for the varlous compounds are set forth in the 20 following table:

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1 From the preceding, it will be seen that~ in accordance with the present invention, a class of novel 5-pyrimidinecarboxamides and thiocarboxamide~ is provided, members of which exhibit substantial cytotoxic activity, and induce regression and/or inhibit growth of leukemia and various malignant 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 chemical substitution, of the active compound~ of the invention.
10 Accordinglyl the preceding disclosure should be construed as illustrative only, and the scope of the invention should be interpreted in accordance with the claims appended hereto.

Claims (26)

1. A process for the production of a compound of the formula:
wherein R1 and R2 are each independently hydrogen;
alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moleties of which have from one to six carbon atoms, or a carbohydrate residue;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl: or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur: and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting a thiourea of the formula R2NH?NHR1 with (1) aN arylaminocarbonylpropanedioic acid diester R4NHCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R4NHCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R4NHCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R4NHCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R4NHCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acld diester R4NHCSCH(CS2R7)(CO2R7), wherein R4 is as defined above and R7 is lower alkyl;
(b) reacting an S-substituted pseudo thiourea wherein R' is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R4NHCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R4NHCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R4NHCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R4NHCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R4NHCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R4NHCSCH(CS2R7)(CO2R7), wherein R4 is as defined above and R7 is lower alkyl, to form the correcponding 2-substituted thiopyrimidinyl compound:
and reacting the 2-substituted thiopyrimidinyl compound with hydrogen sulfide or an alkali metal or ammonium salt thereof;
(c) alkylating a compound of the formula:

to produce a 2-(alkylthio)-substituted compound of the formula reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:
;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof: and (d) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:
with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

2. A process for the production of a compound of the formula:
wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl: or thienylmethyl;
W, Y and Z are each indepandently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting a 2-thiobarbituric acid compound:
wikh an isocyanate R4NCO or isothiocyanate R4NCS in the presence of a solvent or dispersing medium:
(b) reacting a thiourea of the formula R2NH?NHR1 with (1) an arylaminocarbonylpropanedioic acid diester R4NHCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R4NHCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R4NHCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R4NHCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R4NHCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R4NHCSCH(CS2R7)(CO2R7), wherein R4 is as defined above and R7 is lower alkyl;
(c) reacting an S-substituted pseudo thiourea wherein R1 is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R4NHCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R4NHCOCH(Cs2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R4NHCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R4NHCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R4NHCSCH(CS2R7)2, or (6) an arylaminothiorarbonylpropanoic dithioic acid diester R4NHCSCH(CS2R7)(CO2R7), wherein R4 is as defined above and R7 is lower alkyl, to form the corresponding 2-substituted thiopyrimidinyl compound:
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:
to produce a 2-(alkylthio)-substituted compound of the formula reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:
;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof; and (e) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:
with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

3, A compound of the formula:
wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms: carboxy, alkoxycarbohyl having from two to five carbon atoms: nitro:
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl: naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof.

4. 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 3 in admixture with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

5. A pharmaceutical composition for inducing regression of leukemia and inhibition of the growth of tumors in mammals, which comprises a therapeutically effective amount of a compound of the formula:
wherein R1 and R2 are each independently alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms, or a carbohydrate residue;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, in admixture with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

6. The process of Claim 1, which comprises synthesis (a).

7. The process of claim 2, which comprises syntheses (a) or (b).

8. The compound of Claim 3, whenever prepared by syntheses (a) or (b),

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. A process for the production of a compound of the formula:
wherein R1 and R2 are each independently hydrogen:
alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms, or a carbohydrate residue;
R3 is hydrogen, C1-C4 alkyl or aryl:
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting a thiourea of the formula R2NH?NHR1 with (1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3 R4NCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7)(CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl;
(b) reacting an S-substituted pseudo thiourea wherein R1 is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7)(Co2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanehisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7)(CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl, to form the corresponding 2-substituted thiopyrimidinyl compound:
and reacting the 2-substituted thiopyrimidinyl compound with hydrogen sulfide or an alkali metal or ammonium salt thereof;
(c) alkylating a compound of the formula:
to produce a 2-(alkylthio)-substituted compound of the formula:
reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:

;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof; and (d) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:

with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

11. The process of Claim 10, which comprises synthesis (a).

12. A process for the production of a compound of the formula:

wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano: aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting a 2-thiobarbituric acid compound:

with an isocyanate R4NCO or isothiocyanate R4NCS in the presence of a solvent or dispersing medium:
(b) reacting a thiourea of the formula with (1) an arylaminocarbonylpropanedioic acid diester (R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NNCSH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7)(CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl;
(c) reacting an S-substituted pseudo thiourea wherein R' is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7)(CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7)(CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl, to form the corresponding 2-substituted thiopyrimidinyl compound:

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:

to produce a 2-(alkylthio)-substituted compound of the formula:

reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:

;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof; and (e) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:

with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

13. The process of Claim 12, which comprises syntheses (a) or (b).

14. A compound of the formula:

wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms: nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;

W, Y and Z are each independently oxyyen or sulfur; and the pharmacologically acceptable addition salts thereof.

15. The compound of Claim 14, whenever prepared by syntheses (a) or (b).

16. 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.

17. 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 15 in admixture with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

18. A pharmaceutical composition for inducing regression of leukemia and inhibition of the growth of tumors in mammals, which comprises a therapeutically effective amount of a compound of the formula:

wherein R1 and R2 are each independently alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms, or a carbohydrate residue;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl, or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, in admixture with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

19. A process for the production of a compound of the formula:

wherein R1 and R2 are each independently hydrogen;
alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms, or carbohydrate residue;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting a thiourea of the formula with (1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7) (CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7) (CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl;
(b) reacting an S-substituted pseudo thiourea wherein R' is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7) (CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2' (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7) (CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl, to form the corresponding 2-substituted thiopyrimidinyl compound:

and reacting the 2-substituted thiopyrimidinyl compound with hydrogen sulfide or an alkali metal ammonium salt thereof;
(c) alkylating a compound of the formula:

to produce a 2-(alkylthio-substituted compound of the formula reacting the resulting product with an isocyanate R42NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:

;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof; and (d) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:

with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

20. A process for the production of a compound of the formula:
wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl, benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting a 2-thiobarbituric acid compound:

with an isocyanate R4NCO or isothiocyanate R4NCS in the presence of a solvent or dispersing medium;
(b) reacting a thiorea of the formula with (1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2 ) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7) (CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7) (CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl;
(c) reacting an S-substituted pseudo thiourea wherein R' is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH (CO2R7)2, (2) an arylaminocarbonylpropanabisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7) (CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH(CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7) (CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl, to form the corresponding 2-substituted thiopyrimidinyl compound:

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:

to produce a 2-(alkylthio)-substituted compound of the formula reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamide or 5-thiocarboxamido moiety, having the formula:

;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof; and (e) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:

with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

21. A compound of the formula:

wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;

alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof.

22. 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 21 in admixture with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

23. A pharmaceutical composition for inducing regression of leukemia and inhibition of the growth of tumors in mammals, which comprises a therapeutically effective amount of a compound of the formula:

wherein R1 and R2 are each independently alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms, or a carbohydrate residue;

R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, in admixture with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

24. A process as in claim 1 for the production of a compound of the formula:

wherein R1 is hydrogen;

alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl, alkenyl or alkynyl moieties of which have from one to six carbon atoms;
R2 is hydrogen; alkyl, aryl, aralkyl, allyl, aralkenyl or aralkynyl, the alkyl,alkenyl or alkynyl moieties of which are one to six carbon atoms; or a carbohydrate residue;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl: or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy: halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy:
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; ayl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl: or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reacting an S-substituted pseudo thiourea wherein R' is lower alkyl, with:
(1) an arylaminocarbonylpropanedioic acid diester R3R4,NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7) (CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic Acid diester R3R4NCSCH(CS2R7)2, or (6) an Arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH(CS2R7) (CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl;
to form the corresponding 2-substituted thiopyrimidinyl compound:

and reacting the 2-substituted thiopyrimidinyl compound with hydrogen sulfide or an alkali metal or ammonium salt thereof;
(c) alkylating a compound of the formula:

to produce a 2-(alkylthio)-substituted compound of the formula reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:

;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof, and (d) raacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide:
with hydrogon sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

25. A process as in claim 2 for the production of a compound;
of the formula:

wherein Ra and R2 are hydrogen atoms or carbohydrate residues;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy:
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof, which process comprises a process chosen from the group consisting of (a) reactlng a 2-thiobarbituric acid compound:

with an isocyanata R4NCO or isothiocyanate R4NCS in the presence of a solvent or dispersing medium;

(b) reacting an S-substituted pseudo thiourea wherein R' is lower alkyl, with:

(1) an arylaminocarbonylpropanedioic acid diester R3R4NCOCH(CO2R7)2, (2) an arylaminocarbonylpropanebisdithioic acid diester R3R4NCOCH(CS2R7)2, (3) an arylaminocarbonylpropanoic dithioic diester R3R4NCOCH(CS2R7) (CO2R7), (4) an arylaminothiocarbonylpropanedioic acid diester R3R4NCSCH(CO2R7)2, (5) an arylaminothiocarbonylpropanebisdithioic acid diester R3R4NCSCH (CS2R7)2, or (6) an arylaminothiocarbonylpropanoic dithioic acid diester R3R4NCSCH (CS2R7) (CO2R7), wherein R3 and R4 are as defined above and R7 is lower alkyl, to form the corresponding 2-substituted thiopyrimidinyl compound:

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:

to produce a 2-(alylthio)-substituted compound of the formula reacting the resulting product with an isocyanate R4NCO or a thioisocyanate R4NCS to form a compound incorporating the desired 5-carboxamido or 5-thiocarboxamido moiety, having the formula:

;and reacting the compound thus formed with hydrogen sulfide or an alkali metal or ammonium salt thereof; and (e) reacting the corresponding 2-aminopyrimidinecarboxamide or thiocarboxamide::

with hydrogen sulfide or an alkali metal or ammonium salt thereof to displace the amino group therefrom.

26. A compound of the formula:

wherein R1 and R2 are hydrogen atoms or carbohydrate residues;
R3 is hydrogen, C1-C4 alkyl or aryl;
R4 is phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; or phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl substituted with one or more of the following groups:
hydroxy; halo; alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy having from one to four carbon atoms; carboxy;
alkoxycarbonyl having from two to five carbon atoms; nitro;
cyano; aryl; aryloxy; arylthio; benzyl; benzyloxy;
naphthylmethyl; naphthylmethyloxy; thienyl; or thienylmethyl;
W, Y and Z are each independently oxygen or sulfur; and the pharmacologically acceptable addition salts thereof.