CA1248104A - 4-oxo-6-(methylthio) pyrimidine derivatives and process for the preparation thereof - Google Patents

Abstract

ABSTRACT
Herein is disclosed 4-oxo-6-(methylthio)pyrimidine derivatives. The derivatives are useful for producing amino-pyrimidine derivatives which are useful for increasing cardiac contractility in a mammal. The process for their preparation is also disclosed.

Description

~ ~4~3~04 B ack~round of the Invention This invention relates to novel amino-pyrimidine derivatives, to therapeutically acceptabie addition salts thereof, to processes for their preparation, to methods of using said derivatives, methods of using prior 5 reported amino-pyrimidine derivatives and to pharmaceutical compositions of all said derivatives. These derivatives are useful as cardiotonic agents for increasing cardiac contractility.
Although the amino-pyrimidine derivatives of this invention are novel compounds, a number of pyrimidines and 4-oxopyrimidines are described, for lO example, B. Rogge et al., Chem. Abstr. 81, 25691m (1974) for East German patent 101,894, November 20, 1973; S. Kisaki et al., Chem. Pharm. Bull., 22, 2246 (1974); Derwent Publications Ltd., Farmdoc 62457W for German Offenlegenshift 2,410~650, published September 11, 1975; Derwent Publications Ltd., Farmdoc 05783J for Japanese Patent 7,176,981, published October 10, 15 1982; Derwent Publications Ltd., Farmdoc 10368U for Netherland Patent 7,210,637, published February 6, 1973; Chemical ~bstracts, 75, 49129m (1971) for Japanese Patent 7,108,698, published March 5, 1971; A. Kumar et al., Synthesis, (9), 748 (1980); Derwent Publications Ltd., Farmdoc 46076R for East German Patent 72,790, published May 5, 1970; and Derwent Publications Ltd., 20 Farmdoc 31812R for British Patent 1,189,188, published November 9, 1966. The pyrimidines described in the above reports are distinguished from the compounds of this invention by the different substituents on the pyrimidine ring and the reported biological activity~ The amino-pyrimidine derivatives of this inventionare also distinguished from the cardiotonic pyridinones, exemplified by &.Y.
25 Lesher et al., United States Patent 4,072,746, February 7, 1978 and G.Y. Lesher et al., United States Patent 4,313,951, February 2, 1982, by having different rings and different substitution on the rings.

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Most of the 6-amin~S-pyrimidinecarbonitrile derivatives for which a novel use is claimed in this invention are qescribed by Derwent Publications Ltd., Farmdoc 46076R for East German Patent 72,790, published May 5, 1970 as chemical intermediates for the production of physiologically active substances.

5 Summar~ of the Invention The novel compounds of this invention are represented by formula I

~R3 Rl~N-(cR5R6) --(c,~7,j~8) --R9 (I) H 1 4 m n in which R1 is lower alkyl, cyclo(lower)alkyl, phenyl(lower)alkyl, or trifluoromethyl; R2 is oxo, thioxo, or imino; R3 is cyano, aminocarbonyl, nitro,methylsulfonyl or aminosulfonyl; R4, R5; R6, R7 and R8 each independently is lO hydrogen or lower alkyl; R9 is lower alkenyl, l-piperidinyl, l-pyrrolidinyl, 1-piperazinyl, lower alkynyl, cyclo(lower)alkyl, 2, 3 or 4-pyridinyl, 2 or 3-furanyl, 2 or 3-indolyl, 2 or 3-thienyl, 5-imidazolyl, 4-morpholinyl, phenyl, phenyl mono- or disubstituted with hydroxy or lower alkoxy, imidazolyl, 4-thiomorpholinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, thiazolyl, oxadiazolyl, 15 thiadiazolyl, isoxazolyl, furazolyl, oxathiazolyl, quinolinyl, isoquinolinyl,pyridopyrimidinyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, benzoxazinyl, benzpyronyl, isoindolyl, or indolazinyl; and m and n each independently is an integer 0 to 2; or a therapeutically acceptable addition salt thereof.
A preferred group of cormpounds of this invention is represented by 20 formula I in which Rl is lower alkyl, cyclo(lower)alkyl or benzyl; R2 is oxo, thioxo or imino; R3 is cyano or aminoGarbonyl; R4, E~6 and R8 each independently is hydrogen or lower alkyl, R5 and R7 are hydrogen; R9 is lower alkenyl, cyclo(lower)alkyl, 2, 3 or 4-pyridinyl, 2 or 3-furanyl, 2 or 3-indolyl, 2 or 3-thienyl, 4-morpholinyl, phenyl or phneyl mono- or disubstituted with hydroxy or 25 lower alkoxy; and m and n each independently is an integer 0 to 2; or a therapeutically acceptable addition salt thereof.

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A more preferred group of compounds of this invention is represented by formula I in which Rl is lower alkyl, cyclo(lower)alkyl or benzyl; R2 is oxo or thioxo; R3 is cyano; R4 , R5 and R are hydrogen;
R6 and R8 each independently is hyarogen or lower alkyl;
R9 is lower alkenyl, 2, 3 or 4-pyridinyl, 2-furanyl, 3-indolyl, 3-thienyl, 4-morpholinyl, phenyl or phenyl mono- or disubstituted with lower alkoxy; and m and n each independently is the integer 0 or 1; or a therapeutically acceptable addition salt thereof.
This invention also relates to the use for increasing cardiac contractility of a prior reported group of compounds of formula I in which Rl is lower alkyl, cyclo(lower)alkyl or benzyl; R is oxo or thioxo;
R3 is cyano; R4 is lower alXyl; R is hydrogen, and m and n is each the integer 0 or a therapeutically acceptable addition salt thereof.
A preferred group of compounds for increasing cardiac contractility is represented by formula I in which Rl is lower alkyl, cyclo(lower)alkyl or benzyl;
R is oxo; R3 is cyano; R is lower alkyl; R is hydrogen and m and n is each the integer 0.
This invention also relates to a pharmaceutical composition comprising a compound of formuia I or a therapeutically acceptable addition salt thereof and a pharmaceutically acceptable carrier.
This invention alsG relates to a method for increasing cardiac contractility in a mammal which comprises administering to the mammal an effective cardiotonic amount of a compound of formula I or a therapeutically acceptable addition salt thereof.
This invention also relates to a process for preparing a compound of formula I~

~Z~l310~
-4a-3 (IV) Rl I SCH3 in which R is lower alkyl, cyclo(lower)alkyl, phenyl (lower)alkyl, or trifluoromethyl; R3 is cyano, nitro, methylsulfonyl or aminosulfonyl which comprises condensing the amidine II

1 ~H2 R -C=NH (II) in which Rl is lower alkyl, cyclo(lower)alkyl, phenyl (lower)alkyl, or trifluoromethyl with compound of formula III
RlOooC R3 ~
~ (III) in which R3 is cyano, nitro, methylsulfonyl or amino-sulfonyl and R10 is lower alkyl, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90C.
The invention also relates to a compound of formula IV.
Detailed Description of the Invention ... _ .. . . _ .
The term "lower alkyl" as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms, preferably one to four carbon atoms, and includes methyl, ethyl, propyl, l-methyl-ethyl, butyl, l,l-dimethylethyl, pentyl and the like, unless stated otherwise.

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The term "lower alkenyll- as used herein means straight chain alkenyl radicals containing from two to six carbon atoms and branched chain alkenyl radicals containing three to six carbon atoms and includes ethenyl,

2-methyl-2-propenyl, 4-hexenyl and the like.
The term "lower alkynyl" as used herein means straight chain alkynyl radicals containing from two to six carbon atoms and branched chain alkynyl radicals containing four to six carbon atoms and includes ethynyl, 2-propynyl, 1-methyl-2-propynyl, 3-hexynyl and the like.
The term "cyclollower)alkyl" as used herein means saturated cyclic hydrocarbon radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "lower alkanol" as used herein means both straight and branched chain alkanols containing from one to four carbon atoms and includes methanol, ethanol, l-methylethanol, butanol and the like.
The term "inorganic proton acceptor" as used herein means the inorganic bases, preferably the alkali methyl hydroxides, alkoxides, carbonates and bicarbonates, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydride, sodium methoxide and the like.

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~ he compounds of this invention are capable of forming acid addition salts with therapeutically acceptable acids. The acid addition saIts are prepared by reacting the base form of the appropriate compound of formula I with one or more equivalents, preferably with an e.Ycess, of the appropriate acid in an organic solvent, for example, diethyl ether or an ethanol-5 diethyl ether mixture.
These salts, when administered to a mammal, possess the same pharmacologic activities as the corresponding bases. For many purposes : it is preferable to administer the salts rather than 'he basic compounds.
._.
Suitable acids to form these salts include the common mineral acids, e.g.
10 hydrohalic, sulfuric or phosphoric acid; the organic acids, e.g. maleic, citric or tartaric acid; and acids which are sparingly soluble in body fluids and which impart slow-release properties to their respective salts, e.g. pamoic or tannic acid or carboxymethyl cellulose. The addition salts thus obtained are the functional equivalent of the parent base compound in respect to 15 their therapeutic use. Hence, these addition salts are included within the scope of this invention and are limited only by the requirement that the acids employed in forming the salts be therapeutically acceptable.
The compounds of formula I in which R2 is oxo or thioxo are also capable of forming addition salts with sodium or potassium. These 20 salts are prepared by reacting the latter compounds of formLla I with one or more equivalents of sodium or potassium, or a strong base of sodium or potassium, for example, sodium hydroxide, potassium t-buto~ide, sodium hydride and the like. These salts, like the acid addition salts, when administered to a mammal possess the same pharmacological activities as the corres-- 25 ponding nonsalt compound of formula I.
The compounds of formuIa I or a therapeutically acceptable addition salt thereof are useful as cardiotonic agents for increasing cardiac contractility in a mammal. The cardiotonic effect is demonstrated in standard pharmacological tests, for example, in causing an increase in the contractile 30 force of the isolated cat papillary muscle and reversal of pentobarbital-induceè
cardiac failure in the dog.

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The compounds of formula I of this invention are used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubil;ty and chemical nature of the com-pound, chosen route of administration and standard biological practice. For example, they are administered orally in the form of suspensions or solutions 5 or they may be injected parenterally. For parenteral administration they can be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
The tablet compositions contain the active ingredient in admixture with non-toxic pharmaceutical excipients known to be suitable in the manu-10 facture of tablets. Suitable pharmaceutical excipients are, for example,starch, milk sugar, certain types of clay and so fvrth. The tablets can be uncoated or they can be coated by known techniques so as to delay disintegrationand absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
The aqueous suspensions of the compounds of formula I contain the active ingredient in admixture with one or more non-toxic pharmaceu-tical excipients known to be suitable in the manufacture of aqueous sus-pensions. Suitable excipients are, for example, methylcellulose, sodium alginate, gum acacia, lecithin and so forth. The aqueous suspensions can 20 also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents Non-aqueous suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, for example liquid paraffin, and the 25 suspension may contain a thickening agent, for example beeswax, hard paraf-fin or cetyl alcohoL These compositions can aLso contain a sweetening agent, flavoring agent and antioxidant.
The dosage of the compounds of formula I as cardiotonic agents will vary with the form of administration and the particular compound chosen.
,o Furthermore, it will vary with the particular host as well as the age, weightand condition of the host under treatment as well as with the nature and ., ~ . .

..

248~V4 e~tent of the symptoms. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosa,,e is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally S afford effective results without causing any harmful or deleterious side effects. For example, the effective cardiotonic amount of the compounds for oral administration can usually range from about 0.05 to 50 mg per kilogram body wei~ht per day in singlè or divided doses although as aforementioned variations will occur. However, a dosage level that is in the range of from 10 about 0.2 to 20 mg per kilogram body weight per day in single or divided doses is employed most desirably for oral administration in order to achieve effective results.
The compounds of formula I also can be used to produce beneficial effects in the treatment of congestive heart failure when combined with 15 a therapeutically effective amount of another agent commonly used in the treatment of congestive heart failure. Such agents include, for example vasodilators, i.e. isosorbide dinitrate, captopril, nifedipine, hydralazine and prazosin; diuretics, i.e. hydrochlorothiazide, furosemide and spironolactone;
and other cardiotonics, i.e. digitalis and dobutamine. A combination of 20 the above agents can be substituted for a single agent. Suitable methods of administration, compositions and dosages of the agents are well known in the art; for instance, "Physican Desk Reference", 37 ed., Medical Economics Co., Oradell, N.J., U.S.A., 1983. When used in combination, the compound of formula I is administered as described previously.
The compounds of formula I are prepared in the following manner.
Reaction scheme 1 illustrates a method for p~eparing some of the compounds of formula I.

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Reaction Scheme 1 ~H2 RlOooC \ R3 N/~ R3 R -C = NH ~ li/ ll ¦
H3CS ~ ~SCH3 Rl~\N--SCH
I I I) / ( IV) / H-N- (CR5R6) - (CR7R8) -R9

3 ~ R4 (V) N J~

Rl ~N ~ N-~CR R ) -(CR R ) -R
H R
(I) in which R is oxo and R3 is cyano, nitro, methylsulfony~
or aminosulfonyl With reference to reaction scheme 1, the amidine of formuls II in which Rl is as defined herein is condensed with compound of formula III in which R3 is cyano, nitro, methylsulfonyl or aminosulfonyl and Rl is lower alkyl to obtain the pyrimidine OI formula IV in which RI is as defined herein and R3 is cyano, nitro, methylsulfonyl or aminosulfonyl accordin~
to tlhe method described by S. Kisaki et al., Chem. Pharm. Bull., 22, 2246 (1974). This condensation is preferably achieved by reacting about equimolar amounts of the compounds of formulae Il and m in the presence of an inorganic proton acceptor, for example, sodium hydride, sodium aLcoxide or potassium carbonate, in an inert organic solvent, for example, ethanol or dimethyl-formamide, at about 20 to 90 C for about two to ten hours.

~2~

Re~3ction of the pyrimidine of formula IV in which Rl is as defined herein and R is cyano, nitro, methylsulfonyl or aminosulfonyl with the amine of formula V in which R4 to R9, m and n are as defined herein gives the corresponding compound of formula I in which R2 is oxo, R3 is cyano, nitro, methylsulfonyl or aminosulfonyl and Rl, R4 to R9, m and n are as defined 5 herein. About one to five equivalents of the amine of formula V are usually used and the reaction is conducted in an inert organic solvent, preferably 1,2-dimethoxyethane, at about 50 to 100 C for about 10 to 30 hours.
- Reaction Scheme 2 illustrates another method for preparing some of the compounds of formula I
Reaction Scheme 2 R10Ooc R3 ~ H-N-~CR5R6) -~CR7R8) -R9 - ) H_CS SCH3 ~III) ~V) \/ 3 -Rl- C-NH
20 H3CS N- ~CR5R6~m- (CR7R ) n~R9 NH2 CVI) R ~ I I) o N~ R
RlJ~N/~ N-~CR R ) -(CR R ) -R

H
I in which R2 is oxo and R3 is cyano, nitTo~ methylsulfonyl or 3Q aminosul~onyl ,.

~;~4~

With reference to reaction scheme 2, the compound of formula III in which R3is cyano, nitro, methylsulfonyl Ol aminosulfonyl and R10 is lower alkyl is reacted with the amine of formula V in which R4 to R9, m and n are as definedherein to obtain the corresponding compound of formula VI in which R3 is cyano, 5 nitro, methylsulfonyl or aminosulfonyl and R4 to RlO, m and n are as defined herein. For this reaction, preferably about equimolar amounts of the compounds of formulae III and V are allowed to react at about 20 to 40C for about ten minutes to two hours in an inert organic solvent, preferably dimethoxyethane, and the compound of formula YI is isolated.
Condensation of the compound o formula VI in which R3 is cyano, nitro, methylsulfonyl or aminosulfonyl and R4 to RlO, m and n are as defined herein with the amidine of formula II in which Rl is as defined herein gives thecorresponding compound of formula I in which R2 is oxo; R3 is cyano, nitro, methylsulfonyl or aminosulfonyl; and Rl, R4 to R9, m and n are as defined 15 herein. When conducting this condensation, preferably about equal molar amounts of the compounds of formula II and VI are condensed at about 75 to 150C for about 20 to 3û hours in an inert organic solvent, preferably dimethylformamide.
To convert the compound of formula I in which R2 is oxo to the 2Q corresponding compound of formula I in which R2 is thiox~, the following chemical reactions are required. In the first step, the sodium salt of the compound of formula I in which R2 is oxo is reacted with an excess of phosphorous oxychloride at about 90 to 120C for about one to five hours to obtain the corresponding 4-chloropyrimidine derivative. Treatment of the latter 25 derivative with a solution of water and ethanol containing an excess of potassium hydroxide and hydrogen sulfide at about 20 to 40C for about 20 to 30 hours gives the corresponding compound of formula I in which R2 is thioxo; R3 is cyano, nitro, methylsulfonyl or aminosulfonyl; and Rl, R4 to R9, m and n are as defined herein.
Treatment of the above 4-chloropyrimidine with a solut;on of an inert organic solvent, preferably a lower alkanol, containing an excess of ammonia at about 50 to 80C for about 20 to 30 hours gives the corresponding . ~
.

~2q~

compound of formula I in which R2 is imino; R3 is cy~no, nitro, methylsul-fonyl or aminosulfonyl; and Rl, R to R9, m and n are as defined herein.
Hydrolysis of the compound of formula I in which R3 is cyano;
and Rl, R2, R4 to R9, m and n are as defined herein, preferably with sulfuric acid at about 60 to 100 C for one to ten hours, gives the corresponding com-5 pound of formula I in which R3 is aminocarbonyl; and Rl, R2, R to R9,m and n are AS defined herein.
The following examples illustrate further this invention.

10 1,4-Dihydro-2-methyl-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile (IV:
Rl = Me and R3 = cyano) To a suspension of hexane washed sodium hydride (1.46 g, 50%
in oil, l.g eq) in dimethylformamide ~DMF, 1.5 mL) was added dropwise a solution of acetamidine hydrochloride (1.66 g, 1.1 eq) in DMF (7 mL). The 15 reaction mixture was stirred at room temperature for 1 hr. A solution of 2-cyano-3, 3-bis(methylthio)-2-propenoic acid, methyl ester (described by R. Gompper et al., Chem. Ber., 95, 2861 (1962), 3.24 g, 1 eq) in DMF (5 mL, prepared by warming) was added dropwise. Some reaction occurred (evident by gas evolution) during addition. The reaction mixture was allowed to stir 20 at room temperature for 4 hr and diluted with water (13 mL). After acidifi-cation with conc. hydrochloric acid (1.5 mL), the precipitate was collected and dried (2.2 g). Th.s was combined with 2.8 g obtained from another such batch and crystallized from DMF (25 ml)/diethyl ether (30 mL), to yield the title compound (3.8 g): mp> 280 C and Anal. Calcd for C7H7N30S:
25 C, 46.39% H, 3.89% N, 23.19% and Found: C, 46.39% H, 3.79% N, 23.27%.

1,4-Dihydro-2-methyl-4-oxo-6-[(3-pyridinylmethyl)amino] -5-pyrimidinecarbo-nitrile (I: Rl = Me, R2 = o, R3 = CN, R4 to R8 = H, m = 1, n = O and R9 =
3-pyridinyl) }0 To a solution of 1,4-dihydro-2-methyl-6-(methylthio)-4-ox~5-pyrimidinecarbonitrile (described in Example 1,1 eq, 4~4 g) in dimethoxyethane ~5 ~.24~

(33 mL) was added 3-aminomethylpyridine (9.87 mL or 10.53 g, 4 eq). The reaction mi:~ture was refluxed for 18 hours. After about 2 hr of reflux the product started to precipitate. The reaction was cooled after~l8 hr and diluted with methanol &2 mL), and the precipitate was filtered. The pre-cipitate was washed with diethyl ether, and dried to yield white solid (5.97 g).5 A crystallization from hot dimethylformamide yielded the title compound:
mp ~ 260 C; Anal. Calcd for C12HllH50: C, 59.74'o 11, 4.60~o N~ 29.03%
and found: C, 59.41% H, 4.75% N, 29.0896; IR (mineral oil) 3320, 2800, 2210, 1660 cm 1; UV max (MeOH) 289 nm ( 7250); 268 (8300); 263 (8200); 226 (40800); NMR (DMS~d6) ô 12.2 (lH, b), 8.5 (lH, b), 8.45 (2H, m), 7.5 (2H, l0 m), 4.6 12H, d), 2.25 (3H, s).
A suspension of the title compound (0.120 g, 1 eg) in methanol (1 mL), was stirred with methanolic hydrogen chloride (2N, 1 mL, 4 eq) added to it. The reaction mixture was stirred for 1.5 hr, diluted with diethyl ether (5 m~), and filtered. The solid was washed with diethyl ether, to yield crude 15 product (0.16 g). Crystallization from methanol-water yielded the hydro-chloride salt of the title compound (0.1 g): mp ~ 250; and Anal. Calcd for C12HllN50.HCl: C, 51.89% H, 4.32~6 N, 25.22a'o and Found: C, 51.81~6 H,

4.38~6 N, 25.18%.
To a stirred suspension of the title compound (0.491 g, 1 eq) in 20 methanol (2 mL), was added a solution of sodium in methanol (2N, 1.99 mL, 1 eq). The solid went into solution over a period of 0.5 hr. The mixture was stirred overnight during which time some precipitate appeared. Diethyl ether (3 mL) was added, and the sodium salt (0.58 g) was filtered. One cry-stallatization from methanol-diethyl ether yielded the sodium salt of the 25 title compound (Q.44 g): IR (mineral oil) 3660, 3630, 3420, 3320, 2850 cm 1;
and UV max (MeOH) 28~ nm ( C6680), 267 (7670), 263 (75~0), 226 (38050).
In the same manner, but replacing 3-aminomethylpyridine with an equivalent amount of 3-N-methylaminomethylpyridine, 2-phenylethylamine, 2-(2-pyridinyl)ethylamine, 4-aminomethylpyridine, 2-aminomethylpyridine, 30 benzylamine, 2-aminomethylfuran, N-(2-aminoethyl)morpholine, cyclohe~ane-methylamine, 3-(2-aminoethyl)thiophene, 2-(3,4-dimethoxyphenyl)ethylamine, 3-(2-aminoethyl)indole, (3-pyridinyl)ethylamine, (4-pyridinyl)ethylamine, .

:.-~2~81~

the following compounds of formula I were obtained, respectively- 1,4-dihydro-2-methyl-6-[N-methyl-N-(3-pyridinylm ethyl)amino] -4-oxo-5-pyrimidinecarbo-nitrile: mp 256-258 C (cryst. from methanol); IR (mineral oil) 2900, 2200, 1645 cm 1; UV max (MeOH) 291 nm ( ~ 8490), 269 (9510), 263 (8950), 234 (32200); NMR (DMSO-d6) ~ 11.4 (br, lH), 8.0 (m, 4H), 4.95 (s, 2H), 3.25 (s, 3H), 2.2 (s, 3H); Anal. Calcd for C13H13N50: C, 61.1696 H, 5.13% N, 27.44%
and Found: C, 60.846 H, 5.15~o N, 27.37%;1,4-dihydro-2-methyl-4-o~o-6-[(phenylethyl)amino]-5-pyrimidinecarbonitrile: mp 264-266 C (cryst. from methanol); NMR (DMSO-d6) ~ 12.0 (br, lH), 7.8 (t, lH), 7.2 (m, 5H), 3.55 (m, 2H~, 2.8 (t, 2H), 2.2 (s, 3H); Anal. Calcd for C14H14N4O: C, 66.12% HJ

5.5S% N, 22.03% and Found: C, 66.11~6 H, 5.60% N, 21.84%;1,4-dihydro-2-methyl-4-ox~6-[(2-pyridinylethyl)amino]-S-pyrimidinecarbonitrile: mp 276-278 C (cryst. from methanol); IR (mineral oil) 3310, 28S0, 2220,1673 cm 1;
Anal- Calcd for C13H13N50: C, 61.16~6 H, 5.13% N, 27.43~,o and Found C, 60.92'o H, S.15% N, 27.1596;1,4-dihydro-2-methyl-4-oxo-6-[(4-pyridinylmethyl)-15 amino]-5-pyrimidinecarbonitrile hydrochloride: mp~ 250 G (cryst. from methanol-water); UV max (MeOH) 228nm (~ 7110), 2S5 (8220), 22S (42790);
Anal. Calcd for C12HllN50.HCl: C, 51.90% H, 4.35% N, 25.22~6 and Found:
C, 51.826 H, 4.4396 N, 25.36~ 4-dihydro-2-methyl-4-oxo-6-t(2-pyridinyl-methyl)amino]-5-pyrimidinecarboitrile: mp~ 250 C (cryst. from DMF-diethyl 20 ether); NMR (DMSO-d6) ~ 2.15 (s, 3H), 4.68 (2H), 7.2 (2H), 7.7 (lH), 8.22 (lH), 8.47 (lH); Anal. Calcd for C12HllN50: C, 59.74% H, 4.60~6 N, 29.03~Yo and Found: C, 59.69% H, 4.78% N, 28.83%;1,4-dihydro-2-methyl-4-oxo-6-[(phenylm ethyl)amino] -5-pyrimidinecarbonitrile: mp ~ 290 C (cryst. from DMF); NMR (DMSO-d6) ~ 8.3 (t, lH), 7.25 (s, 5H), 4.57 (d, 2H), 2.2 (s, 3H);
25 Anal- Calcd for C13H12N40: C, 64-98% EI, 5.04% N, 23.32% and Found: C, 64.84% H, 5.27% N, 23.28%;1,4-dihydro-6-t(2-furanylmethyl)amino]-2-methyl-4-oxo-S-pyrimidinecarbonitrile: mp 297-300 C (cryst. from methanol); NMR
(DMS~d6) ~ 2.2 (s, 3H), 4.55 (d, 2H), 6.25 (m, 2H), 7.5 (m, IH), 8.2 (t, lH), 11.4 (br, lH); Anal. Calcd for CllH~oN4O2: C, 57.38~6 H, 4.38% N, 24.34~6 30 and Found: C, 57.02% H, 4.49~6 N, 24.159~;1,4-dihydro-2-methyl-6-[[2-(4-morpholinyl)ethyl] amino] -4-o~;~5-pyrimidinecarbonitrile: mp 227-230 C
(cryst. from methanol-acetonitrile); NMR (CDC13) ~ 2.4 (s, 3H), 2.5 (m, ~248~04 6H), 3.65 (m, 6H), 3.35 (t, lH); IR (mineral oil) 3340, 2850,1670,1595 cm 1;
Anal. Calcd for C13H18N40: C, 63.39% H, 7.36% N, 22.75% and Found C
63.56,o H, 7.32~6 N, 22.64%;1,4-dihydro-2-methyl-4-ox~6-[E2-(3-thienyl)-ethyl~ amino]-5-pyrimidinecarbonitrile: mp 290-292 C; NMR (DI~So~6j 2.2 (s, 3H), 2.8 (t, 2H), 3.55 (m, 2H), 7.15 (m, 3H), 7.8 (t, lH); Anal. Calcd for C12H12N40S: C, 55.36% H, 4.659~ N, 21.52~6 and Found: C, 55.07% H, 4.61% N, 21.36~6;1,4-dihydro-6-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-methyl-4-oxo-5-pyrimidinecarbonitrile: mp 238-240 C (cryst. from methanol);
NMR (DMS~d6) C 2.2 (s, 3H), 2.7 (t, 2H), 3.5 (m, 2H), 3.7 (s, 3H), 3.73 (s, 3H), 6~75 (m, 3H), 7.7 (t, lH); Anal. Calcd for C16H18N03: C, 61.14~6 H, 5.77 N, 17.829~ and Found: C, 60.63% H, 5.73% N, 17.68%;1,4-dihydro-6-[[2-(lH-indol-3-yl)ethyl] amino] -2-methyl-4-oxo-5-wrimidinecarbonitrile; mp 297-300 C (cryst. from methanol); NMR (DMS~d6) ~ 2.2 (s, 3H), 2.9 (t, 2H), 3.6 (m, 2H), 7.1 (m, 4H), 7.85 (t, lH), 10.75 (s, lH), 11.5 (br, lH); Anal. Calcd for C16H15N50: C, 65.51~6 H, 5.11'o N, 23.88% and Found: C, 65.14~6 H, 5.219 N, 23.78%; I,4-dihydro-2-methyl-4-oxo-6-[2-(3-pyridinyl)ethylamino]-S-py-rimidinecarbonitrile: mp ~ 250 C (cryst. from DMF); UV max (MeOH) 227 nm ~ ~ 38,300), 263 (8000), 269 (8000), 290 (6800); NMR (DMSO~6) ~ 2.2 (s, 3H), 2.85 (t, 2H), 3.6 (m, 2H), 7.25 (m, lH), 7.6 (m, lH), 7.85 (br, lH), 8.4 (m, 2H); Anal. Calcd for C13H13N5O: C, 61.16% H, 5.13% N, 27.43% and ~ound:
C, 60.62% H, 5.12% N, 27.36%;1,4-dihydro-2-methyl-4-oxo-6-[2-(4-pyridinyl)-ethylamino]-5-pyrimidinecarbonitrile: mp~ 250C (cryst. from DMF); UV
msx (MeOH) 226 nm ( ~ 32,700), 257 (6370), 263 (6670), 289 (6870); NMR
(DMS~d6) 2.2 (s, 3H), 2~82 (t, 2H~, 3.6 (m, 2H), 7.18 (2d, 2HJ, 7.83 (br, IH), 8.42 (2d, 2H), 11.5 (br, lH); Anal. Calcd for C13H13N50: C9 61.15% H, 5-13% N, 27-43% and Found: C, 61.23% H, 5.20% N, 27.41~6.

I,4-Dihydro-2-methyl-4-oxo-6-[(2-propenyl)amino] -5-pyrimidinecarbonitrile (I:Rl=Me,R2=O,R3=CN,R4toR8=H,m=l,n=O,andR9=ethenyl) To a suspension of 2-cyano-3,3-bis(methylthio~-propenoic acid, methyl ester (8.12 g) in dimethoxyethane (13 mL~ was added (2-propenyl)amine (2.51 g). The mixture dissolved. After about 15 min the solvent was evaporated ,.~

-~24~04 under nitrogen and the solid residue was filtered with diethyl ether to give 2-cyano-3-methylthio-3-(2-propenyl)amino-2-propenoic acid, methyl ester (8.61 g~.
Similarly, but replacing (2-propenyl)amine with 3-aminopyridine, the following compound of formula VI was obtained; 2-cyano-3-methylthio-3-(3-pyridinyl)amino-2-propenoic acid, methyl ester: mp 93-94 C.
To a suspension of acetamidine hydrochloride (1.25 g, 1.1 eq) in DMF (45 mL) was added 2-cyano-3-methylthio-3-(2-propenyl)amino-2-pro-penoic acid, methyl ester (12.54 g, 1 eq) and potassium carbonate (1.82 g, 2.2 eq). The mixture was heated to 130 C for 22 hr, cooled in an ice water 10 bath and diluted with water (20 mL). The precipitate was collected (0.7 g).
The filtrate was evaporated and suspended in a small amount of water (7 mL) and filtered to give more product (0.3 g). The product was crystallized from DMF to yield the title compound (0.44 g): mp~ 260 C; UV max (MeOH) 289 nm ( F 6610), 269 (5640), 227 (42640j; NMR (Dl~S~d63 ~ 2.2 (s, 3H), 15 3.95 (m, 2H), 5.05 (m, 2H), 5.8 (m, lH), 7.9 (t, lH); Anal. Calcd for CgHloN40 C, 56.84% H, 5.2696 N, 29.47% and Found: C, 56.58% H, 5.34~ N, 29.56%.
Similarly, replacement of 2-cyano-3-methylthio-3-(2-propenyl)-amino-2-propenoic acid, methyl ester with 2-cyano-3-methylthio-3-(3-pyridinyl~
amino-2-propenoic acid, methyl ester, the following compound of formula 20 I was obtained: 1,4-di~ydro-2-methyl-4-oxo-6-[(3-pyridinyl)amino]-5-pyrimidine-carbonitrile: mp~ 260 C (cryst. from DMF); IR (mineral O 3320, 2700, 2210,1695 cm 1; NMR (DMS~d6) ~ 2.2 (s, 3H), 7.9 (m, 4H), 9.75 (br, 2H);
Anal. Calcd for C~lHgN50: C, 58.09% H, 3.99% N, 30.82~6 and Found: C, 57.80% H, 4.18% N, 30.36%.

4-Amino-2-methyl-6-~(3-pyridinylm ethyl)amino] -5-pyrimidinecarbonitrile (I: Rl = Me, R2 = NH, R3 = CN, R4 to R8 = H, m = 1, n = O and R9 = 3- pyridinyl)To phosphorous oxychloride (42.9 g, or 26.1 mL, 8 eq) preheated to 100 C (bath temp.) was added, the sodium salt of 1,4-dihydro-2-methyl-30 4-oxo-6-~(3-pyridinylm ethyl)amino] -5-pyrimidinecarbonitrile (described in Example 2), (9.2 g, 1 eq). The reaction mixture was heated for 2 hr. The solution was cooled and poured into ice water ~900 mL) with stirring. The '' , :: .

~2~ 04 resulting solution was basified with sodium hydroxide (50%~100 mL). Some ethyl acetate was added, and the resulting precipitate was filtered and dried to yield a solid (4.7 g). The aqueous filtrate was extracted with ethyl acetate,and the extract was dried and evaporated to give a residue ~1.8 g). The com-bined material was crystallized from chloroform-hexane to give 4-chloro-2-methyl-6-~(3-pyridinylm ethyl~amino] -5-pyrimidinecarbonitrile: mp 165-167 C; UV max (MeOH) 305 nm (F 4130), 254 (18100).
A solution of the latter compownd (1.5 g, 1 eq) in methanol (25 mL) was cooled in an ice bath. Ammonia was passed into the solution for 20 min. The reaction mixture turned yellow. The mixture was heated in 10 a closed container to 60 C for 2 hr. The precipitate began to appear con-comitently with discoloration. The mixture was stirred at room temperature overnight. The solvent was removed, water was added, and the solid was f~tered to give crude product (1.~ g). Three crystallizations from DrYIF yieldedthe title compound (0.3 g): mp ~ 28Q C; UV max (MeOH) 254 nm ( 12740), lS 234 (44070); Anal. Calcd for C12H12N6: C, 59.98% H, 5.04% N~ 34.98% and Found: C, 59.50~6 H, 5.13% N, 34.41%.
EXAMPL~ 5 1,4-Dihydro-2-m ethyl-6-[(3-pyridinylm ethyl)amino] -4-thiox~5-pyrimidinecarbo-nitrile~I:Rl=Me,R2=S,R3=CN~R4toR8=H,m=l,n=o~andR9=
20 3-pyridinyl) To ethanol (5 mL) was added a solution of potassium hydroxide (l.S mL, 4 molar in water-ethanol 1:9). The mixture was cooled in ice-bath.
Hydrogen sulphide was passed through the soIution for lS min. 4-Chloro-2-methyl-6-[(3-pyridinylmethyl)amino]-5-pyrimidinecarbonitrile (described 25 in Example 4, 0.73 g, 1 eq) in ethanol (7 mL) was added to the solution. The mixture WflS stirred at room temperature for 2.5 hr. Another portion of potassium hydroxide solution (1.5 mL) in ethanol (3.5 mL) was added. Hydrogen sulfide passed through for lS min. It was stirred overnight at room temper-ature. The mixture was filtered and the precipitate was washed with some 30 ethanol, to yield crude product ~0.7 g). The solid was crystallized twice from DMF to yield the title compound (0.25 g): mp 310-312 C; NMR (DMSO_d6)~

~81~4 13.2 (br, lH), 8.8 (br, IH), 8.5 (m, 2H), 7.5 (m, 2H), 4.6 (dJ 2H), 2.3 (s, 3H);Arlal. Calcd for C12HllN5S: C, 56.01~6 H, 4.31~6 NJ 27.2296 and Found C, 55.48~ H, 4.49% N, 26.6896.

1,4-Dihydro-2-methyl-~-ox~6-[(3-pyridinylmethyl)amino] -5-pyrimidinecar-5 boxamide (I: Rl = Me, R2 = O, R3 = aminocarbonyl, R4 to R8 = H, m = 1, n = O, and R9 = 3-pyridinyl) Sulfuric acid (4 mL) was added to 1,4-dihydro-2-methyl-4-oxo-

6-[(3-pyridinylmethyl)amino~-5-pyrimidinecarbonitrile (1.2 g, described in Example 2). The mixture was heated to 70 C for 4 hr. The reaction was 10 cooled to room temperature, and carefully poured on crushed ice (75 mL).
The resulting solution was neutralized with sodium hydroxide (50%, aqueous, 12.5 mL) when precipitate appeared. Filtrate a~ter removal of precipitate showed the pH to be 4.5-5Ø Eight more drops of sodium hydroxide were added. More precipitate appeared. This was filtered off. The pH was checked 15 and found to be 5. One more drop changed the pH to 8. The combined solid was dried and crystallized from boiling DMF to yieId the title compound (1.1 g): mp 264-266; Anal. Calcd for C12H14N5O2: C, 55-38% H, 5-38% N, 26.9% and Found: C, S5.26% H, 5.I2% N, 26.70%; IR (mineral o~) 3760, 3000, 1645,1585 cm 1; NMR (DMSO-d6) ~ 8.5 (lH, m), 7.55 ~lH, m), 7.25 (lH, m~, 20 9.15 (lH, m~, 4.7 (2H, d), 2.22 (3H, s).

2-Methylpropanimidamide (Il: Rl = l-methylethyl) Anhydrous hydrogen chloride was passed into a solution of 2-methylpropanenitrile (30.4 g, 40 mL) in anhydrous ethanol (25 mL) until saturation at 25 C. The stoppered reaction mixture did not crystallize after 3 days and was evaporated to dryness under reduced pressure. The oily residue crystallized after a while and was treated with a lQ% solution of anhydrous ammonia in ethanol (130 mL). After stirring for 3 hr, ammonium chloride was filtered off, and the filtrate was concentrated ~til crystalline.
30 The first batch of the product (2a~.7 g) was collected by filtration, the second batch (9.6 g) r,!as obtained on further concentration of the filtrate to give a total yield of the hydrochloride salt of the title compound (34.3 g): mp 155-1S7 C.

~Z4~33104 Similarly, by replacing 2-methylpropanenitrile with propanenitrile, 2,2-dimethylpropanenitrile, cyclopropylnitriIe, or 2-phenylethanenitrile, the following cornpounds of formula Il were obtained respectively: propanimid-.
amide hydrochloride (mp 13~-132 C), 2,2-dimethylpropanimidamide hydro.
chloride (mpl86-188C), cyclopropylmethanimidamide hydrochloride (mp 123-125 C), and 2-phenylethanimidamide hydrochloride (mp 145-147 C).

1,4-Dihydro-2-(1-methylethyl~6-(methylthio~4-ox~5-pyrimidinecarbonitrile (IV: Rl = l-methylethyl) A solution of 2-methylpropanimidamide hydrochloride (7.0 g, 10 described in Example 7) in dimethylformamide (15 mL) was added dropwise to a suspension of sodium hydride (3.0 g, 50% in mineral oil, prewashed with hexane) in dimethylformamide (15 mL) and the whole mixture was left at 25 C for 1 hr. 2-Cyano-3,3-bis(methylthio~2-propenoic acid, methyl ester (6.5 g) in dimethylformamide (15 mL) was then added dropwise, and the reaction 15 mixture was stirred for an additional 4 hr at 25 C. Water (25 mL) was then added, and acidi~ication with concentrated hydrochloric acid (10 mL) precipi-tated the product. The precipitate was collected and air dried to give the title compound (6.0 g): mp ~ 260 C.
Similarly, by replacing 2-methylpropanimidamide with another 20 compound of form-da described in Example 7, the following compounds of formula IV were obtained respectiYely: 1,4-dihydro-2-ethyl-6-(methylthio~
4-ox~5-pyrimidinecarbonitrile (mp ~ 26 0 C), 1,4-dihydro-2 (1,1~im ethyl-ethyl~6-(methylthio~4-oxo-5-pyrimidinecarbonitrile (mp ~ 360 C), 2-cyclo-propyl-1,4-dihydro-6-(methylthio~4-ox~5-pyrimidinecarbonitrile tN~qR
25 (DMS~d6) ~ 1~2 (d, 4H)~ 2.0 (m, lH), 2.5 (s, 3H)], and 1,4-dihydro-6-(methyl- thio~4-oxo-2-(phenylmethyl~5-pyrimidinecarbonitrile [NMR (DMSO-d6) 2.6 (s, 3H), 4.0 (s, 2H~, 7.4 (s, 5H)~.

1,4-Dihydro-2-(1-methylethyl~4-oxo-6-[(3-pyridinylm ethyl)amino] -5-pyrimidine-30 carbonitrile (I: Rl ~ l-methylethyl, R2 = o, R3 = CN, R4 to R8 = H, m =
1, n = O, and R9 = 3-pyridinyl) ~2~810~

3-(Aminomethyl)~pyridine (16 mL) was added to 1,4-dihydro-2-(l-methylethyl~6-(methylthio~4-oxo-5-pyrimidinecarbonitrile (6 g~ described in Example 8) in 1,2-dimethoxyethane (50 mL), and the mixture was refluxed overnight. Evaporation to dryness under reduced pressure gave the crude product which was chromatographed over silica acid with chloroform-meth~nol 5 (97:3~. The product was isolated as a colo~less solid which was crystallized from methanol-water to give the title compound (3.4 g): mp ~ 260 C; NMR
(DMS~d6) ~ 1.1 (d, 6H), 2.7 (m, IH), 4.55 (m, 2H), 7.3-8.4 ~m, 4H), 11.5 (br, 2H); IR (mineral oil) 3335, 2900, 2210,1660,1585 cm li Anal. Calcd for C14H15-N50: C, 62.44% H, 5.61~6 N, 25.94% and Found: C, 62.12~6 H, 5.63% N, 25.92~.
Sirnilarly, by replacing 1,4-dihydro-2-(1-methylethyl~6-(methylthio~
4~xo-5-pyrimidinecarbonitrile with another compound of formula IV described in Example 8, the following compounds of formula I were obtained respectively:
1,4-dihydro-2-ethyl-4-oxo-6-[(3-pyridinylm ethyl)amino] -5-pyrimidinecarbo-nitrile hydrochloride: mp ~ 265 C (cryst. from methanol-water); NMR (DMSO~6)~
15 1.05 (t, 3H), 2.45 (d, 2H), 4.75 (d, 2H), 6.2 (br, 2H), 8.4 (m, 4~),11.4 (br, lH);
IR (mineral oil) 3280, 2600, 2220, 2080, lg60, 1650 cm 1; Anal. Calcd for C13H14ClN3O: C, 53.52% H, 4.84% N, 24~00% and Found: C, 53.17% H, 4.84~6 N, 23.74%; 1,4-dihydro-2-~1,1-dim ethylethyl~4-oxo-6-[(3-pyridinylm ethyl~
amino] -5-pyrimidinecarbonitrile hydrochloride: mp ~ 260 C (cryst. from 20 methanol-water); NMX (DMS~d6) ~ L17 (s, 9H), 4.15 (d, 2H), 8.5 (m, 4H), 8.6 (br, lH), 8.9 (br, lH), 11.9 (s, lH); ~ (mineral oil) 3280, 3180, 3100, 2600, 2220, 2100,1970,1660 cm~l; Anal. Calcd for C18~17N5O: C, 56.34% H, 5.67%
N, 21.90% and Found: C7 57.74% H, 5.61% N, 21.96%; 2-cyclopropyl-1,4-dihydr~
4-oxo-6-[(3-pyridinylmethyl)amino] -5-pyrimidinecarbonitrile: mp ~ 260 C
25 (cryst- from 1,2-dimethoxyethane); NMR (DMS~d6) ~ 1.0 (m, 4H), 1.8 (m, lH), 4.5 (d, 2H)i 7.5-8.5 (m, 4H), 12.4 (br, lH3; IR (mineral o~ 3300, 2850, 2190,1685 cm ; Anal. Calcd for C14H13N5O: C, 62.91% H, 4.90% N, 26.2Q%
and Found: C, 62.31~ H, 4.90% N, 25.98q6; and 1,4-dihydro-4-oxo-2-(phenyl-m ethyl~6-[(3-pyridinylm ethyl)amino~ -5-pyrimidinecarbonitrile: mp > 26 0 C
30 (cryst. from acetonitrile); NMR (DMS~d6) ~ 3.8 (s, 2H), 4.5 (d, 2H), 7.25 ~2~ 04 (s, 5H), 7.45 and 8.4 (m, 4H), 8.4 (br, lH); IR (mineral oil) 3330, 2800, 2210, 1660, 1590 cm~l; Anal. Calcd for C18H15N50: C, 68.13% ~, 4.76% N, 22.07% and Found: C, 67.83% H, 4.~2% N, 21.85%.

5 1,4-Dihydr~6-(ethylamino~2-methyl-4-oxo-5-pyrimidinecarbonitrile (1: Rl =
Me,R2= o,R3=H andR4=Et) To a suspension of 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (8.12 g, 1 eq) in dimethoxyethane (14 mL) was added a solution of ethylamine (2.16 g, 1.2 eq.) in dimethoxyethane (6.5 mL). The suspension turned o to ~olution, and a white solid began to precipitate. After about 10 min the solvent was removed and the residue was filtered with diethyl ether to yield 2-cyano-3-ethylamino-3-methylthio-2-propenoic acid, methyl ester (7.2 g): mp 86-88C.
To a solution of acetamidine hydrochloride (0.83 g, 1.1 eq) in DMF (5.5 mL) was added potassium carbonate (1.22 g, 2.2 eq) and the mixture was stirred at room temperature for about 10 min. The above cyanoester ~1.6 g, 1 eq) was added and the mixtùre was heated to 90 C overnight. The reaction mixture was cooled, diluted with water and filtered to give a solid (0.3 g). Further concentration to dryness followed by filtration of residue with small amount of 20 water gave more solid (0.8 g). The two solids were pooled and crystallized from methanol to give the title compound (0.6 g): mp> 290C; Anal. Calcd. for C8HloN4O: C, 53.93% H, 5.61% N, 31.46% and Found: C, 53.67% H, 5.83%
N, 31.31%; IR (mineral oil) 3300, 2800, 2220, 1650 cm~l; WAmax (MeOH) 289 nm (~ 6140), 268 (5240), 226 (40,100); NMR (DMSO-d6) o7.75 (t, IH), 3.4 (m, 2H), 25 2.23 (s, 3H), 1.1 (s, 3H).
Similarly, the foJlowing compounds of formula I can be prepared: 1,4-dihydro-6-(butylamino)-2-cyclohexyl-4-oxo-5-pyrimidinecarbonitrile, 1,4-dihydro-6-(diethylamino~-2-butyl-4-oxo-5-pyrimidinecarbonitrile, 1,4-dihydro-6-(N-methyl-N-propylamino~2-benzyl-4-oxo-5-pyrimidinecarbonitrile, and 1,4-30 dihydro-6~propylamino)-2-cyclopropyl-4-oxo-5-pyrimidinecarbonitrile.

-~2~8~L04 Test for Cardiotonic Activity in Isolated Cat Papillary Muscle A cat of either sex was anesthetized with Na pentobarbital, 25-30 mg/kg i.v. The heart was rapidly removed and placed in cool Tyrode's solution 5 which had been equilibrated with 95% 2-5% CO2. The right ventricle was opened by cutting down the sides and around the apex so that the free ~vall could be folded back on the atriventricular groove. Usually at least three suitably-sized papillary muscles were found (1 mm or less in thickness). Threads were tied around the chordae tendonae and the base f the muscle just above its point 10 of insertion into the ventricular wall. The chordae were cut, and the muscle was removed along with a small button of ventricular wall. If a sufficient number ofpapillary muscles were not present, trabeculae carnae could also be used. The best ones were usually found inserting just under the valve.
The preparations were mounted in tissue baths containing Tyrode's 1~ solution at 37C bubbled with 95% 2-5% CO~ One thread was affixed to a tissue holder incorporating a pair of platinum eleetrodes and the other thread was attached to a force displacement transducer. Initial tension placed on the preparation was 0.2 g (less for very small muscles). The preparations were stimulated with square-wave pulses, 2-4 msec. in duration and 10% above 20 threshold voltage, at a rate of 0~5Hzo The muscles were then gently and gradually stretched to their optimum force-length relation (at which twitch tension was maximal~further stretching did not result in any further increase inthe overall magnitude of the twitch). The preparations were then allowed to equilibrate for one hour with frequent changes of the bathing fluid (10-15 min 25 intervals). The test compound was added to the bath in 0.1 mL of vehicle and incubated with the preparation for 15 min or until peak effect was attained.
Using this method, the following representative compounds of formula I
were effective for increasing the force of contraction of the papillary muscle tthe amount of test compound in the bath and increase in contractility is given in 3~ the parenthesis): 1,4-dihydro-2-methyl-4-oxo-6-[(3-pyridinylmethyl)amin~l-5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 98%), 1,4-dihydr~2-methyl-4-oxo-6-[(4-pyridinylmethyl)amino] -5-pyrimidinecarbonitrile 12~8~04 tat 10-4 molar increased contractility by 139%), 1,4-dihydro-2-methyl-4-oxo-6-[(phenylethyl)aminc3-5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 142%), 1,4-dihydro-2-ethyl-4-oxo-6-1(3-pyridinylmethyl)amin~l-5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 140%), 1,4-5 dihydro-6-[(2-furanylmethyl)amino]-2-methyl-4-oxo-5-pyrimidinecarbonitrile (at10-4 molar increased contractility by 108%, 2-cyclopropyl-1,4-dihydro-4-oxo-6-[~3-pyridinylmethyl)amino]-5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 129%), 1,4-dihydro-2-methyl-6-[(2-(4-morpholinyl)ethy~amin~l-4-ox~5 pyrimidinecarbonitrile (at 10-4 molar increased contractility by 62%), 10 1~4-dihydro-2-methyl-4-oxo-6-[[2-(3-thienyl)ethy~amin~l-5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 149%), 1,4-dihydro-2-methyl-4-oxo-6-[(2-propenyl)amino]-5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 61%) and 1,4-dihydro-6-(ethylamino~2-methyl-4-ox~5-pyrimidinecarbonitrile (at 10-4 molar increased contractility by 88%).
~X~MPLE 12 Pentobarbital-induced Cardiac Failure in the Dog A dog of either sex was anesthetized with Na pentobarbital, 30-35 mg/kg i.v. The trachea was intubated and the animsl was respired at a rate of 20 breaths/min (stroke volume = 15 cc/kg). Both femoral veins were cannulated.
20 One cannula was used for infusion of pentobarbital to induce and maintain failure, the other for injection of test compounds. A cannula was inserted into the aort~ via a femoral artery and the cannula was attached to a blood pressure transducer for measurement of systolic, diastolic and mean aortic blood pressure. A Millar pressure-tip catheter was inserted into the other femoral 25 artery and ad~lanced into the left ventricle to record intraventricular pressure and dP/dt. Subdermal needle electrodes were used to record a lead II
electrocardiogram and heart rste.
Following a stabilization period of at least 30 min, experimentsl failure wss induced by the i.v. infusion of Na pentobarbital, 0.~5 mg/kglmin in 0.2 mL of 30 saline/min, until a 40-50% decrease in peak positive dP/dt was obtained. The failure state was maintained at this level throughout the experiment by continuous infusion of Na pentobarbital, 0.11-0.15 mg/kg/min. Once the maintenance infusion was started, at least 15 min were allowed to elapse before test drugs were administered.

.

~24~3~04 Test compounds were prepared in N saline. Increasingly higher doses were given i.v. at 30 min-lhr intervals in order to determine a therapeutic (50%increase in dP/dt) to toxic (appearance of arrhythmias) ratio where po~sible.
U~ing thi~ method, the following representative compounds of formula T
5 were effective for increasing the cardiac contractility of the heart (the amount of test compound in mg per kg of body weight administered i.v. to give a 50%
increase in dP/dt is given in the parenthesis): 1,4-dihydro-2-methyl-4-oxo-6-[(3-pyridinylmethyl)aminc~-5-pyrimidinecarbonitrile (0.06 mg/kg), 1,4-dihydro-2-methyl-4-oxo-6-[(4-pyridinylmethyl)amino]-5-pyrimidinecarbonitrile (0.07 10 mg/kg), 1,4-dihydro-2-ethyl-4-oxo-6-[(3-pyridinylmethyl)aminc3-5-pyrimidinecarbonitrile (0.05 mg/kg), 1,4-dihydro-6-[(2-furanylmethyl)aminil-2-methyl-4-oxo-5-pyrimidinecarbonitrile (0.06 mg/kg), 2-cyclopropyl-1,4-dihydro-4-oxo-6-[(3-pyridinylmethyl)amino]-5-pyrimidinecarbonitrile (0.02 mg/kg), 1,4-dihydro-2-methyl-4-oxo-6-[[2-(3-thienyl)ethy~ amin~l-5-pyrimidinecarbonitrile 15 (0.08 mg/kg), and 1,4-dihydro-6-(ethylamino)-2-methyl-4-oxo-5-pyrimidine-carbonitrile (0.02 mg/kg).
This application is a division of Canadian Appli-cation No. 457, 551 filed June 27, 1984.

:

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of formula IV
(IV) in which R1 is lower alkyl, cyclo(lower)alkyl, phenyl (lower)alkyl, or trifluoromethyl; R3 is cyano, nitro, methylsulfonyl or aminosulfonyl which comprises condensing the amidine II
(II) in which R1 is lower alkyl, cyclo(lower)alkyl, phenyl (lower)alkyl, or trifluoromethyl with compound of formula III
(III) in which R3 is cyano, nitro, methylsulfonyl or amino-sulfonyl and R10 is lower alkyl, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C.

2. A process for preparing the compound 1,4-dihydro-2-methyl-6-(methylthio)-4-oxo-5-pyrimidine-carbonitrile which comprises condensing acetamidine with 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C to obtain the desired compound.

3. A process for preparing the compound 1,4-dihydro-2-(1-methylethyl)-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile which comprises condensing 2-methylpropanimidamide with 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C to obtain the desired compound.

4. A process for preparing the compound 1,4-dihydro-2-ethyl-6-(methylthio)-4-oxo-5-pyrimidinecarbo-nitrile which comprises condensing propanimidamide with 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C to obtain the desired compound.

5. A process for preparing the compound 1,4-dihydro-2-(1,1-dimethylethyl)-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile which comprises condensing 2,2-dimethylpropanimidamide with 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C to obtain the desired compound.

6. A process for preparing the compound 2-cyclo-propyl-1,4-dihydro-6-(methylthio)-4-oxo-5-pyrimidine-carbonitrile which comprises condensing cyclopropyl-methanimidamide with 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C to obtain the desired compound.

7. A process for preparing the compound 1,4-dihydro-6-(methylthio)-4-oxo-2-(phenylmethyl)--5-pyrimidinecarbonitrile which comprises condensing 2-phenylethanimidamide with 2-cyano-3,3-bis(methyl-thio)-2-propenoic acid, methyl ester, in the presence of an inorganic proton acceptor in an inert organic solvent at about 20 to 90°C to obtain the desired compound

8. A compound of formula IV

(IV) in which R1 is lower alkyl, cyclo(lower)alkyl, phenyl-(lower)alkyl, or trifluoromethyl; R3 is cyano, nitro, methylsulfonyl or aminosulfonyl.

9. The compound 1,4-dihydro-2-methyl-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile.

10. The compound 1,4-dihydro-2-(1-methyl-ethyl)-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile.

11. The compound 1,4-dihydro-2-ethyl-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile.

12. The compound 1,4-dihydro-2-(1,1-dimethylethyl)-6-(methylthio)-4-oxo-5-pyrimidine-carbonitrile.

13. The compound 2-cyclopropyl-1,4-dihydro-6-(methylthio)-4-oxo-5-pyrimidinecarbonitrile.

14. The compound 1,4-dihydro-6-(methyl-thio)-4-oxo-2-(phenylmethyl)-5-pyrimidinecarbonitrile.